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Sample records for adjuvant tamoxifen monotherapy

  1. Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy.

    PubMed

    Thompson, Alastair M; Johnson, Andrea; Quinlan, Philip; Hillman, Grantland; Fontecha, Marcel; Bray, Susan E; Purdie, Colin A; Jordan, Lee B; Ferraldeschi, Roberta; Latif, Ayshe; Hadfield, Kirsten D; Clarke, Robert B; Ashcroft, Linda; Evans, D Gareth; Howell, Anthony; Nikoloff, Michele; Lawrence, Jeffrey; Newman, William G

    2011-01-01

    The association between CYP2D6 genotype and outcome in breast cancer patients treated with adjuvant tamoxifen remains controversial. We assessed the influence of comprehensive versus limited CYP2D6 genotype in the context of tamoxifen adherence and co-medication in a large cohort of 618 patients. Genotyping of 33 CYP2D6 alleles used two archival cohorts from tamoxifen-treated women with invasive breast cancer (Dundee, n = 391; Manchester, n = 227). Estimates for recurrence-free survival (RFS) were calculated based on inferred CYP2D6 phenotypes using Kaplan-Meier and Cox proportional hazard models, adjusted for nodal status and tumour size. Patients with at least one reduced function CYP2D6 allele (60%) or no functional alleles (6%) had a non-significant trend for worse RFS: hazard ratio (HR) 1.52 (CI 0.98-2.36, P = 0.06). For post-menopausal women on tamoxifen monotherapy, the HR for recurrence in patients with reduced functional alleles was 1.96 (CI 1.05-3.66, P = 0.036). However, RFS analysis limited to four common CYP2D6 allelic variants was no longer significant (P = 0.39). The effect of CYP2D6 genotype was increased by adjusting for adherence to tamoxifen therapy, but not significantly changed when adjusted for co-administration of potent inhibitors of CYP2D6. Comprehensive genotyping of CYP2D6 and adherence to tamoxifen therapy may be useful to identify breast cancer patients most likely to benefit from adjuvant tamoxifen.

  2. Linking Estrogen-Induced Apoptosis With Decreases in Mortality Following Long-term Adjuvant Tamoxifen Therapy

    PubMed Central

    2014-01-01

    The impressive first results of the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) and the adjuvant Tamoxifen To offer more (aTTom) trials both demonstrate that 10 years of tamoxifen is superior to five years of treatment. Tamoxifen is a nonsteroidal antiestrogen that blocks estrogen-stimulated tumor growth. Paradoxically, mortality decreases dramatically only in the decade after long-term tamoxifen is stopped. It is proposed that the evolution and clonal selection of micrometastases that acquire tamoxifen resistance now become increasingly vulnerable to endogenous estrogen-induced apoptosis. Laboratory and clinical studies confirm the concept, and supporting clinical evidence from the estrogen-alone trial in the Women’s Health Initiative (WHI), demonstrate that long-term estrogen-deprived women given exogenous physiologic estrogen have a decreased incidence of breast cancer and decreased mortality. It is proposed that a natural process of apoptosis is recruited to execute the long-term survival benefit of stopping ten years of adjuvant tamoxifen, but only after clonal selection of vulnerable breast cancer cells in an estrogen-deprived environment. PMID:25269699

  3. Factor V Leiden Mutation and Thromboembolism Risk in Women Receiving Adjuvant Tamoxifen for Breast Cancer

    PubMed Central

    Halabi, Susan; Tolaney, Sara M.; Kaplan, Ellen; Archer, Laura; Atkins, James N.; Edge, Stephen; Shapiro, Charles L.; Dressler, Lynn; Paskett, Electra M.; Kimmick, Gretchen; Orcutt, James; Scalzo, Anthony; Winer, Eric; Levine, Ellis; Shahab, Nasir; Berliner, Nancy

    2010-01-01

    Background Tamoxifen use has been associated with increased risk of thromboembolic events (TEs) in women with breast cancer and women at high risk for the disease. Factor V Leiden (FVL) is the most common inherited clotting factor mutation and also confers increased thrombosis risk. We investigated whether FVL was associated with TE risk in women with early-stage breast cancer who took adjuvant tamoxifen. Methods A case–control study was conducted among 34 Cancer and Leukemia Group B (CALGB) institutions. We matched each of 124 women who had experienced a documented TE while taking adjuvant tamoxifen for breast cancer (but who were not necessarily on a CALGB treatment trial) to two control subjects (women who took adjuvant tamoxifen but did not experience TE) by age at diagnosis (±5 years). DNA from blood was analyzed for FVL mutations. Conditional logistic regression was used to estimate odds ratios (ORs) and to evaluate other potential factors associated with TE and tamoxifen use. All P values are based on two-sided tests. Results FVL mutations were identified in 23 (18.5%) case and 12 (4.8%) control subjects (OR = 4.66, 95% confidence interval = 2.14 to 10.14, P < .001). In the multivariable model, FVL mutation was associated with TE (OR = 4.73, 95% confidence interval = 2.10 to 10.68, P < .001). Other statistically significant factors associated with TE risk were personal history of TE and smoking. Conclusions Among women taking adjuvant tamoxifen for early-stage breast cancer, those who had a TE were nearly five times more likely to carry a FVL mutation than those who did not have a TE. Postmenopausal women should be evaluated for the FVL mutation before prescription of adjuvant tamoxifen if a positive test would alter therapeutic decision making. PMID:20554945

  4. No increased venous thromboembolism risk in Asian breast cancer patients receiving adjuvant tamoxifen.

    PubMed

    Chen, Tom Wei-Wu; Chen, Ho-Min; Lin, Ching-Hung; Huang, Chiun-Sheng; Cheng, Ann-Lii; Lai, Mei-Shu; Lu, Yen-Shen

    2014-11-01

    Tamoxifen is an effective endocrine treatment for early breast cancer (EBC) but increases the risk of venous thromboembolism. Whether Asian EBC patients (pts) bear the same risk when treated with adjuvant tamoxifen is uncertain. EBC pts diagnosed between 2004 and 2009 were selected from a population database in Taiwan. The pts were followed up from the index date to December 31, 2011 to collect events of deep vein thrombosis (DVT) and pulmonary embolism (PE). Cumulative incidence rates and hazard ratios (HRs) were used to compare the risk between pts treated with and without tamoxifen. In addition, comorbidities were included in an adjusted model of the risk of DVT and PE. A total of 28,029 EBC pts, including 17,843 (63.8 %) in the tamoxifen group and 10,155 (36.2 %) in the nontamoxifen group, were analyzed. The 7-year cumulative incidence rates for DVT and PE were 2.58 and 0.32 % in the tamoxifen group and 2.51 and 0.32 % in the nontamoxifen group (P = 0.92 for DVT, P = 0. 65 for PE), respectively. The HR for the nonadjusted and adjusted models showed no differences in DVT and PE risks between the tamoxifen and nontamoxifen groups. The uterine cancer risk was significantly increased in the pts receiving tamoxifen (adjusted HR = 2.79, P < 0.001), suggesting tamoxifen compliance. The risks of developing DVT and PE are not increased in Asian EBC pts receiving adjuvant tamoxifen. Ethnicity differences should be considered when discussing optimal endocrine treatments with EBC pts.

  5. Tamoxifen as the First Targeted Long Term Adjuvant Therapy for Breast Cancer

    PubMed Central

    Jordan, V. Craig

    2014-01-01

    Tamoxifen is an unlikely pioneering medicine in medical oncology. Nevertheless, the medicine has continued to surprise us, perform and save lives for the past 40 years. Unlike any other medicine in oncology, it is used to treat all stages of breast cancer, ductal carcinoma in situ, male breast cancer, pioneered the use of chemoprevention by reducing the incidence of breast cancer in women at high risk and induces ovulation in subfertile women! The impact of tamoxifen is ubiquitous. However, the power to save lives from this unlikely success story came from the first laboratory studies which defined that “longer was going to be better” when tamoxifen was being considered as an adjuvant therapy (Jordan 1978 Use of the DMBA-induced rat mammary carcinoma system for the evaluation of tamoxifen as a potential adjuvant therapy Reviews in Endocrine Related Cancer. October Supplement: 49–55.). This is that success story, with a focus on the interdependent components of: excellence in drug discovery, investment in self-selecting young investigators, a conversation with Nature, a conversation between the laboratory and the clinic, and the creation of the Oxford Overview Analysis. Each of these factors was essential to propel the progress of tamoxifen to evolve as an essential part of the fabric of society. “Science is adventure, discovery, new horizons, insight into our world, a means of predicting the future and enormous power to help others”(Hoagland 1990).- Mahlon Hoagland, MD. Director, Worcester Foundation for Experimental Biology (1970–85) PMID:24659478

  6. Ovarian hyperstimulation in premenopausal women during adjuvant tamoxifen treatment for endocrine-dependent breast cancer: A report of two cases

    PubMed Central

    MADEDDU, CLELIA; GRAMIGNANO, GIULIA; KOTSONIS, PARASKEVAS; PARIBELLO, FRANCESCO; MACCIÒ, ANTONIO

    2014-01-01

    Adjuvant endocrine therapy is an integral component of care for endocrine-dependent breast cancer. The aim of this type of therapy is to counteract the production and the action of estrogens. The ovary is the primary site of estrogen production in premenopausal women, whereas, in postmenopausal women, the main source of estrogens is adipose tissue. Therefore, ovarian function suppression is an effective adjuvant strategy in premenopausal estrogen-dependent breast cancer. Similarly, the inhibition of estrogen action at the receptor site by tamoxifen has proven to be effective. To date, international consensus statements recommend tamoxifen (20 mg/day) for five years as the standard adjuvant endocrine therapy for premenopausal women. It should be noted that tamoxifen is a potent inducer of ovarian function and consequent hyperestrogenism in premenopausal women. In the present study, we report two cases of ovarian cyst formation with very high estrogen levels and endometrial hyperplasia during the administration of tamoxifen alone as adjuvant treatment for estrogen receptor-positive breast cancer in premenopausal women. These cases suggest that in young premenopausal patients with estrogen-dependent breast cancer, ovarian suppression is an essential prerequisite for an adjuvant endocrine therapy with tamoxifen. In this context, luteinizing hormone-releasing hormone agonist treatment by suppressing effective ovarian function may lead to a hypoestrogenic status that may positively impact breast cancer prognosis and prevent the effects of tamoxifen at the gynecological level. It is important to reconsider the action of tamoxifen on ovarian function and include these specific effects of tamoxifen in the informed consent of premenopausal patients who are candidates for tamoxifen alone as adjuvant endocrine treatment. PMID:25120706

  7. Design, conduct, and analyses of Breast International Group (BIG) 1-98: A randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer

    PubMed Central

    Giobbie-Hurder, Anita; Price, Karen N; Gelber, Richard D

    2010-01-01

    Background Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. Purpose To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. Methods From 1998–2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. Results The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. Limitations Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. Conclusions BIG 1-98 is an example of an enriched design, involving

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

    PubMed Central

    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

  9. Subsequent endometrial carcinoma with adjuvant tamoxifen treatment in Japanese breast cancer patients.

    PubMed

    Nishimura, N; Hachisuga, T; Saito, T; Kawarabayashi, T

    2001-01-01

    This study aimed to detail the clinicopathologic features of endometrial carcinomas that developed in Japanese patients receiving adjuvant tamoxifen treatment for breast cancer patients. Ten endometrial carcinomas in tamoxifen-treated breast cancer patients were collected from two medical centers. The endometrial carcinomas included two stage Ia, four stage Ib, two stage Ic and two stage IIIc. Three tumors were Grade 1, six were Grade 2, and one was Grade 3. The tumor was limited to the endometrium in two cases. Myometrial invasion was limited to the inner half of the myometrium in five cases and involved the outer half in three. A mild degree of lymphovascular space invasion was identified in five cases. Deep cervical invasion was recognized in one case. The cell types comprised nine endometrioid adenocarcinomas and one serous carcinoma. Five of eight postmenopausal endometrial carcinomas were associated with polypoid endometrial lesions composed of cystically dilated atrophic and proliferative glands widely separated by fibrotic stroma. Two patients with retroperitoneal lymph node metastases died of endometrial cancer. One patient developed a contralateral breast cancer during tamoxifen treatment. No patient died of breast cancer. We did not demonstrate a higher frequency of either high-grade tumors or unfavorable histologic subtypes in tamoxifen-treated Japanese breast cancer patients.

  10. Obesity and Risk of Recurrence or Death After Adjuvant Endocrine Therapy With Letrozole or Tamoxifen in the Breast International Group 1-98 Trial

    PubMed Central

    Ewertz, Marianne; Gray, Kathryn P.; Regan, Meredith M.; Ejlertsen, Bent; Price, Karen N.; Thürlimann, Beat; Bonnefoi, Hervé; Forbes, John F.; Paridaens, Robert J.; Rabaglio, Manuela; Gelber, Richard D.; Colleoni, Marco; Láng, István; Smith, Ian E.; Coates, Alan S.; Goldhirsch, Aron; Mouridsen, Henning T.

    2012-01-01

    Purpose 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. Patients and Methods This report analyzes 4,760 patients with breast cancer randomly assigned to 5 years of monotherapy with letrozole or tamoxifen in the BIG 1-98 trial with available information on BMI at randomization. Multivariable Cox modeling assessed the association of BMI with disease-free survival, overall survival (OS), breast cancer–free interval, and distant recurrence-free interval and tested for treatment-by-BMI interaction. Median follow-up was 8.7 years. Results Seventeen percent of patients have died. Obese patients (BMI ≥ 30 kg/m2) had slightly poorer OS (hazard ratio [HR] = 1.19; 95% CI, 0.99 to 1.44) than patients with normal BMI (< 25 kg/m2), whereas no trend in OS was observed in overweight (BMI 25 to < 30 kg/m2) versus normal-weight patients (HR = 1.02; 95% CI, 0.86 to 1.20). Treatment-by-BMI interactions were not statistically significant. The HRs for OS comparing obese versus normal BMI were HR = 1.22 (95% CI, 0.93 to 1.60) and HR = 1.18 (95% CI, 0.91 to 1.52) in the letrozole and tamoxifen groups, respectively. Conclusion There was no evidence that the benefit of letrozole over tamoxifen differed according to patients' BMI. PMID:23045588

  11. Tamoxifen

    MedlinePlus

    ... the disease due to their age, personal medical history, and family medical history.Tamoxifen is in a class of medications known ... any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you ...

  12. Improving compliance and persistence to adjuvant tamoxifen and aromatase inhibitor therapy.

    PubMed

    Hadji, Peyman

    2010-02-01

    Better compliance and persistence with therapy are associated with improved patient outcomes. As more and more patients survive breast cancer, compliance with adjuvant therapy becomes increasingly important. In clinical trials, compliance with adjuvant endocrine therapy among women with breast cancer is usually high. Retrospective analyses of databases and medical records from clinical practice, insurance databases of prescription refills, and survey data show a significant decrease in persistence after 12 months of therapy. With ongoing therapy, a further decline in persistence of up to 50% has been reported. A consistent methodology is needed to measure patient behavior and identify patients who are not adhering to therapy. Promising strategies for enhancing adherence to treatment in clinical practice include improving access to health care, increasing patient satisfaction, managing side effects, patient education, and better communication between the patient and health care provider. Positive relationships between patients and their health care providers, and frequent monitoring and feedback, may be most effective. While the lack of conformity across studies in measuring makes cross-study comparisons difficult, this review evaluates the available data regarding compliance and persistence with adjuvant endocrine therapies for breast cancer (tamoxifen and aromatase inhibitors) and presents strategies for improving adherence.

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

    PubMed Central

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

    2016-01-01

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

  14. Health-related quality of life, psychological distress, and adverse events in postmenopausal women with breast cancer who receive tamoxifen, exemestane, or anastrozole as adjuvant endocrine therapy: National Surgical Adjuvant Study of Breast Cancer 04 (N-SAS BC 04).

    PubMed

    Takei, Hiroyuki; Ohsumi, Shozo; Shimozuma, Kojiro; Takehara, Megumi; Suemasu, Kimito; Ohashi, Yasuo; Hozumi, Yasuo

    2012-05-01

    Health-related quality of life (HRQOL), symptoms of depression, and adverse events (AEs) were compared between Japanese postmenopausal patients with hormone-sensitive breast cancer (BC) who received adjuvant tamoxifen, exemestane, or anastrozole in an open-labeled, randomized, multicenter trial designated as the National Surgical Adjuvant Study of Breast Cancer (N-SAS BC) 04 substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. During the first year of treatment, HRQOL and symptoms of depression were analyzed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and its Endocrine Symptom Subscale (ES), and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. In addition, predefined AEs were analyzed. A total of 166 eligible patients were randomly assigned to receive adjuvant tamoxifen, exemestane, or anastrozole. FACT-B scores increased after treatment began and remained significantly higher in the tamoxifen group than in the exemestane group or anastrozole group during the first year (P = 0.045). FACT-B scores were similar in the exemestane group and anastrozole group. ES scores and CES-D scores were similar in all treatment groups. Arthralgia and fatigue were less frequent, but vaginal discharge was more frequent in the tamoxifen group than in the exemestane group or anastrozole group. HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole. HRQOL and AEs were similar with exemestane and anastrozole. Given the results of the TEAM trial, upfront use of tamoxifen followed by an aromatase inhibitor (AI) may be an important option for adjuvant endocrine therapy in Japanese postmenopausal women.

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

    SciTech Connect

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

    1991-07-17

    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.

  16. Cost-effectiveness analysis of anastrozole vs tamoxifen in adjuvant therapy for early stage breast cancer in the United Kingdom: the 5-year completed treatment analysis of the ATAC (‘Arimidex', Tamoxifen alone or in combination) trial

    PubMed Central

    Mansel, R; Locker, G; Fallowfield, L; Benedict, Á; Jones, D

    2007-01-01

    Results from the completed treatment analysis of the ATAC (Arimidex, Tamoxifen alone or in combination) trial indicated that anastrozole was significantly superior to tamoxifen in terms of efficacy and safety in the adjuvant treatment of postmenopausal women with hormone receptor-positive (HR+) early breast cancer. On the basis of these results, this study estimated the cost-effectiveness of anastrozole vs tamoxifen, from the perspective of the UK National Health Service (NHS). A Markov model was developed using the 5-year completed treatment analysis from the ATAC trial (ISRCTN18233230), as well as data obtained from published literature and expert opinion. Resource utilisation data and associated costs (2003–4 UK£) were compiled from standard sources and expert opinion. Utility scores for a number of health states were obtained from a cross-sectional study of 26 representative patients using the standard gamble technique. The utility scores were then inserted into the model to obtain cost per quality adjusted life-year (QALY) gained. Costs and benefits were discounted at recommended annual rates of the UK Treasury (3.5%). Modelled for 25 years, anastrozole, relative to generic tamoxifen, was estimated to result in 0.244 QALYs gained per patient at an additional cost of £4315 per patient). The estimated incremental cost-effectiveness of anastrozole compared with tamoxifen was £17 656 per QALY gained. There was a greater than 90% probability that the cost-effectiveness of anastrozole was below £30 000 per QALY gained and of the order of 65% that it was below £20 000 per QALY gained. The results were robust to all parameters tested in sensitivity analysis. Compared with commonly accepted thresholds, anastrozole is a cost-effective alternative to generic tamoxifen in adjuvant treatment of postmenopausal women with HR+ early breast cancer from the UK NHS perspective. PMID:17622238

  17. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials

    PubMed Central

    Early Breast Cancer Trialists' Collaborative Group (EBCTCG)

    2011-01-01

    Summary Background As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen. Methods We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21 457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment. Findings In oestrogen receptor (ER)-positive disease (n=10 645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 [SE 0·03] during years 0–4 and RR 0·68 [0·06] during years 5–9 [both 2p<0·00001]; but RR 0·97 [0·10] during years 10–14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10–19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 [0·08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 [0·05] during years 0–4, 0·66 [0·05] during years 5–9, and 0·68 [0·08] during years 10–14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality. Interpretation 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the

  18. Antipsychotic monotherapy and adjuvant psychotropic therapies in schizophrenia patients: effect on time to readmission.

    PubMed

    Valevski, Avi; Gilat, Yaron; Olfson, Mark; Benaroya-Milshtein, Noa; Weizman, Abraham

    2012-05-01

    This study assessed the relationship between pharmacological regimens at hospital discharge and hospital readmission among schizophrenia patients. The records reviewed were all consecutive admissions (N=720) from a specific catchment area during the period 1991-2005. Two main groups were selected for analysis: the first group (N=537) included patients discharged with first-generation antipsychotics (FGA), and the second group (N=183) included patients with second-generation antipsychotics (SGA). Data on clinical and demographic characteristics at discharge, including a brief psychiatric rating scale and pharmacological treatment, were collected. The rate of readmission within 12 months was analyzed in relation to the specific pharmacological treatment at discharge. There was no significant difference in the risk of readmission in patients treated with SGA compared with FGA. Adjuvant psychotropic medications to either FGA or SGA did not attenuate the risk of readmission. The readmission rate in patients treated with clozapine (N=74) was significantly lower in comparison with depot FGA (N=293) medications (P=0.016). There was no advantage of SGA over FGA, with or without adjuvant psychotropic treatment, with regard to rehospitalization risk during the 12-month follow-up. Clozapine was found to reduce the risk for readmission in comparison with depot FGA. PMID:22466059

  19. [Administration of S-1 Monotherapy as Adjuvant Chemotherapy in a Patient with Advanced Gastric Cancer with HIV Infection].

    PubMed

    Amaki, Misato; Yajima, Kazuhito; Iwasaki, Yoshiaki; Ken, Yuu; Oohinata, Ryouki; Imamura, Akifumi

    2016-08-01

    A 64-year-old man with advanced gastric cancer presented with chief complaints of chest pain. His preoperative blood examination revealed positive results for serum HIV-antibody. His HIV-RNA level was 1.0×10 / 5 copies/mL, and his CD4lymphocyte count was 491 cell/mL; the patient was diagnosed with advanced gastric cancer and HIV infection. Distal gastrectomy with D2 lymphadenectomy and Roux-en-Y reconstruction were performed for treatment of the gastric cancer. Pathological examination revealed T3(SS)N3aM0, Stage III C cancer. After surgery, the patient was administered S-1 monotherapy as adjuvant treatment with antiretroviral therapy including tenofovir/emtricitabine and raltegravir. He completed 8 courses of S- 1 chemotherapy with no adverse events, such as a decrease in the CD4lymphocyte count or an increase in the HIV-RNA level. This patient with gastric cancer and HIV infection was safely treated using both antiretroviral therapy and chemotherapy owing to treatment intervention by chemotherapy and infectious diseases specialists. PMID:27539043

  20. Prognostic and Predictive Value of Centrally Reviewed Ki-67 Labeling Index in Postmenopausal Women With Endocrine-Responsive Breast Cancer: Results From Breast International Group Trial 1-98 Comparing Adjuvant Tamoxifen With Letrozole

    PubMed Central

    Viale, Giuseppe; Giobbie-Hurder, Anita; Regan, Meredith M.; Coates, Alan S.; Mastropasqua, Mauro G.; Dell'Orto, Patrizia; Maiorano, Eugenio; MacGrogan, Gaëtan; Braye, Stephen G.; Öhlschlegel, Christian; Neven, Patrick; Orosz, Zsolt; Olszewski, Wojciech P.; Knox, Fiona; Thürlimann, Beat; Price, Karen N.; Castiglione-Gertsch, Monica; Gelber, Richard D.; Gusterson, Barry A.; Goldhirsch, Aron

    2008-01-01

    Purpose To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer. Patients and Methods Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%. Results Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09). Conclusion Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy. PMID:18981464

  1. Tamoxifen for breast cancer prevention

    SciTech Connect

    Jordan, V.C.

    1995-02-01

    The case for tamoxifen to be tested as a preventive for breast cancer has merit. Animal studies demonstrate that tamoxifen prevents mammary carcinogenesis and clinical studies now confirm that adjuvant tamoxifen therapy is the only systemic treatment that will prevent contralateral breast cancer. Developing clinical studies confirm the laboratory data that tamoxifen will maintain post-menopausal bone density in the lumbar spine and the neck of the femur; two important skeletal sites for the ultimate prevention of osteoporosis. However, a most important target site-specific effect of tamoxifen is the decrease in low-density lipoprotein cholesterol levels in postmenopausal women. This positive property of tamoxifen may be responsible for the recorded decreases in hospital visits for the treatment of cardiac conditions and the significant decrease in fatal myocardial infarction for women treated with 5 years of adjuvant tamoxifen. These data provide the scientific basis to undertake randomized, placebocontrolled clinical trials to test the worth of tamoxifen to prevent breast cancer.

  2. Hypothalamic-pituitary-ovarian axis in women with operable breast cancer treated with adjuvant CMF and tamoxifen.

    PubMed

    Delrio, G; De Placido, S; Pagliarulo, C; d'Istria, M; Fasano, S; Marinelli, A; Citarella, F; De Sio, L; Contegiacomo, A; Iaffaioli, R V

    1986-02-28

    The effect of adjuvant CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) and tamoxifen (TM) on hypothalamic-pituitary-ovarian function was studied in 120 women with stage I-II operable breast cancer. Sixty patients were premenopausal, of whom 25 were treated with CMF for 9 cycles, 25 with CMF for 9 cycles + TM for 2 years, started concurrently, and 10 with TM alone for 2 years. Sixty patients were postmenopausal and they were all treated with TM alone for 2 years. In all groups treatment was started within 4 weeks of mastectomy. Plasma levels of estrone (E1), estradiol-17 beta (E2), follicle-stimulating hormone, luteinizing hormone (LH), prolactin (Prl), testosterone (T) and thyroid-stimulating hormone (TSH) were determined in all patients before surgery and again at 3-month intervals from initiation of the adjuvant therapy. In ten patients of each treatment group FSH-LH and Prl-TSH release was determined following stimulation with releasing hormones. CMF and CMF+TM therapy resulted in amenorrhea in 42/50 premenopausal patients with decrease of E1+E2 (p less than 0.001) and elevation of FSH (p less than 0.001) and LH (p less than 0.01) plasma concentration to postmenopausal levels. In premenopausal women treated with TM a marked increase of E1+E2 (p less than 0.001) was observed with unaltered FSH-LH plasma concentration. A significant fall of Prl also occurred in these patients. In postmenopausal women and premenopausal patients with CMF-induced amenorrhea TM produced a marked fall of FSH-LH and a decrease of Prl plasma level. Plasma TSH and T were not affected in any patient by any of the treatment regimens. The results of the stimulatory tests are in agreement with the hormonal changes observed under basal conditions and indicate that, whereas CMF suppresses the ovary and does not alter hypothalamic-pituitary function, TM induces profound changes of the hypothalamic-pituitary-ovarian axis.

  3. Adjuvant Surgical Oophorectomy Plus Tamoxifen in Premenopausal Women With Operable Hormone Receptor-Positive Breast Cancer: A Global Treatment Option.

    PubMed

    Love, Richard R

    2016-08-01

    One third of annual new cases of breast cancer globally are now hormone receptor-positive tumors in premenopausal women from low- and middle-income countries. For this subgroup of women with breast cancer, high-income country guidelines suggest impractical and unaffordable adjuvant treatments. The balance of clinical trial evidence now suggests that surgical oophorectomy plus tamoxifen is a safe and practical treatment for these women in low- and middle-income countries. Additionally, new randomized trial data suggest that women in the second half of an anovulatory cycle benefit minimally from surgical oophorectomy done at this time, which implies that regularly cycling women will benefit more than has been shown from this procedure. Allred scoring of levels of hormone receptors is a practical and inexpensive approach to the assessment of magnitudes of response to oophorectomy plus tamoxifen. These circumstances suggest that more detailed consideration of this option should characterize clinical practice guidelines in high-income countries because of their global impact.

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

    PubMed

    Lin, Guigao; Zhang, Kuo; Yi, Lang; Han, Yanxi; Xie, Jiehong; Li, Jinming

    2016-01-01

    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. PMID:27603206

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

    PubMed

    Lin, Guigao; Zhang, Kuo; Yi, Lang; Han, Yanxi; Xie, Jiehong; Li, Jinming

    2016-01-01

    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.

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

    PubMed Central

    Lin, Guigao; Zhang, Kuo; Yi, Lang; Han, Yanxi; Xie, Jiehong; Li, Jinming

    2016-01-01

    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. PMID:27603206

  7. Association of CYP2D6*10 (c.100C>T) polymorphisms with clinical outcome of breast cancer after tamoxifen adjuvant endocrine therapy in Chinese population.

    PubMed

    Lei, Lei; Wang, Xian; Wu, Xiao-Dan; Wang, Zeng; Chen, Zhan-Hong; Zheng, Ya-Bin; Wang, Xiao-Jia

    2016-01-01

    Tamoxifen is the most widely used adjuvant endocrine therapy for breast cancer. However, the pharmacogenetic effect of CYP2D6 on its efficacy remains unclear. Therefore, this study aimed to evaluate the association of CYP2D6*10 (c.100C>T) polymorphisms with clinical outcome in Chinese breast cancer patients. A total of 72 tamoxifen-treated early breast cancer patients were included in this study. CYP2D6*10 (c.100C>T) polymorphisms (C/C: wild type; T/T: homozygous mutant genotype T; C/T: heterozygote genotype C) were detected by pyrosequencing. The plasma concentrations of tamoxifen and its two major active metabolites were determined by liquid chromatography tandem mass spectrometry (LC-MS). Disease-free survival (DFS) and overall survival (OS) were assessed by Kaplan-Meier analysis, while the Cox proportional hazards model was used in multivariate tests for prognostic significance. We found that T/T carrier showed the lowest serum concentration of endoxifen as compared to C/C and C/T carriers (p<0.01). In the subgroup of patients below 40 years of age, T/T carriers appeared to have the shortest DFS and OS as compared to other genotype carriers (p<0.01). When genotypes (C/C, C/T and T/T carriers) and other clinical characteristics were adjusted, tumor size (>2 cm) and grades were independent prognostic factors for DFS but not OS (tumor size >2 cm: HR: 3.870, 95% CI: 1.045-14.330, P = 0.043; tumor grades: HR: 2.230, 95% CI: 1.090-4.562, P = 0.028). In conclusion, the T/T genotype is a negative prognostic factor in young breast cancer patients using tamoxifen. Tumor size (>2 cm) and grades are independent prognostic factors for DFS, when genotype of CYP2D6*10 (c.100C>T) is adjusted. PMID:27648149

  8. Association of CYP2D6*10 (c.100C>T) polymorphisms with clinical outcome of breast cancer after tamoxifen adjuvant endocrine therapy in Chinese population

    PubMed Central

    Lei, Lei; Wang, Xian; Wu, Xiao-dan; Wang, Zeng; Chen, Zhan-hong; Zheng, Ya-bin; Wang, Xiao-jia

    2016-01-01

    Tamoxifen is the most widely used adjuvant endocrine therapy for breast cancer. However, the pharmacogenetic effect of CYP2D6 on its efficacy remains unclear. Therefore, this study aimed to evaluate the association of CYP2D6*10 (c.100C>T) polymorphisms with clinical outcome in Chinese breast cancer patients. A total of 72 tamoxifen-treated early breast cancer patients were included in this study. CYP2D6*10 (c.100C>T) polymorphisms (C/C: wild type; T/T: homozygous mutant genotype T; C/T: heterozygote genotype C) were detected by pyrosequencing. The plasma concentrations of tamoxifen and its two major active metabolites were determined by liquid chromatography tandem mass spectrometry (LC-MS). Disease-free survival (DFS) and overall survival (OS) were assessed by Kaplan-Meier analysis, while the Cox proportional hazards model was used in multivariate tests for prognostic significance. We found that T/T carrier showed the lowest serum concentration of endoxifen as compared to C/C and C/T carriers (p<0.01). In the subgroup of patients below 40 years of age, T/T carriers appeared to have the shortest DFS and OS as compared to other genotype carriers (p<0.01). When genotypes (C/C, C/T and T/T carriers) and other clinical characteristics were adjusted, tumor size (>2 cm) and grades were independent prognostic factors for DFS but not OS (tumor size >2 cm: HR: 3.870, 95% CI: 1.045-14.330, P = 0.043; tumor grades: HR: 2.230, 95% CI: 1.090-4.562, P = 0.028). In conclusion, the T/T genotype is a negative prognostic factor in young breast cancer patients using tamoxifen. Tumor size (>2 cm) and grades are independent prognostic factors for DFS, when genotype of CYP2D6*10 (c.100C>T) is adjusted. PMID:27648149

  9. Association of CYP2D6*10 (c.100C>T) polymorphisms with clinical outcome of breast cancer after tamoxifen adjuvant endocrine therapy in Chinese population

    PubMed Central

    Lei, Lei; Wang, Xian; Wu, Xiao-dan; Wang, Zeng; Chen, Zhan-hong; Zheng, Ya-bin; Wang, Xiao-jia

    2016-01-01

    Tamoxifen is the most widely used adjuvant endocrine therapy for breast cancer. However, the pharmacogenetic effect of CYP2D6 on its efficacy remains unclear. Therefore, this study aimed to evaluate the association of CYP2D6*10 (c.100C>T) polymorphisms with clinical outcome in Chinese breast cancer patients. A total of 72 tamoxifen-treated early breast cancer patients were included in this study. CYP2D6*10 (c.100C>T) polymorphisms (C/C: wild type; T/T: homozygous mutant genotype T; C/T: heterozygote genotype C) were detected by pyrosequencing. The plasma concentrations of tamoxifen and its two major active metabolites were determined by liquid chromatography tandem mass spectrometry (LC-MS). Disease-free survival (DFS) and overall survival (OS) were assessed by Kaplan-Meier analysis, while the Cox proportional hazards model was used in multivariate tests for prognostic significance. We found that T/T carrier showed the lowest serum concentration of endoxifen as compared to C/C and C/T carriers (p<0.01). In the subgroup of patients below 40 years of age, T/T carriers appeared to have the shortest DFS and OS as compared to other genotype carriers (p<0.01). When genotypes (C/C, C/T and T/T carriers) and other clinical characteristics were adjusted, tumor size (>2 cm) and grades were independent prognostic factors for DFS but not OS (tumor size >2 cm: HR: 3.870, 95% CI: 1.045-14.330, P = 0.043; tumor grades: HR: 2.230, 95% CI: 1.090-4.562, P = 0.028). In conclusion, the T/T genotype is a negative prognostic factor in young breast cancer patients using tamoxifen. Tumor size (>2 cm) and grades are independent prognostic factors for DFS, when genotype of CYP2D6*10 (c.100C>T) is adjusted.

  10. 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

    PubMed Central

    Park, Tae Yong; Jeong, Hyeong Guk; Park, Jong Jin; Chae, Ji Yun; Kim, Jong Wook; Oh, Mi Mi; Park, Hong Seok; Kim, Je Jong

    2016-01-01

    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 30° (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 30°. PMID:27169128

  11. Evaluation of CYP2D6 enzyme activity using a Dextromethorphan Breath Test in Women Receiving Adjuvant Tamoxifen

    PubMed Central

    Safgren, Stephanie L.; Suman, Vera J.; Kosel, Matthew L.; Gilbert, Judith A; Buhrow, Sarah A.; Black, John L.; Northfelt, Donald W.; Modak, Anil S.; Rosen, David; Ingle, James N.; Ames, Matthew M.; Reid, Joel M.; Goetz, Matthew P.

    2015-01-01

    Background In tamoxifen-treated patients, breast cancer recurrence differs according to CYP2D6 genotype and endoxifen steady state concentrations (Endx Css). The 13Cdextromethorphan breath test (DM-BT), labeled with 13C at the O-CH3 moiety, measures CYP2D6 enzyme activity. We sought to examine the ability of the DM-BT to identify known CYP2D6 genotypic poor metabolizers and examine the correlation between DMBT and Endx Css. Methods DM-BT and tamoxifen pharmacokinetics were obtained at baseline (b), 3 month (3m) and 6 months (6m) following tamoxifen initiation. Potent CYP2D6 inhibitors were prohibited. The correlation between bDM-BT with CYP2D6 genotype and Endx Css was determined. The association between bDM-BT (where values ≤0.9 is an indicator of poor in vivo CYP2D6 metabolism) and Endx Css (using values ≤ 11.2 known to be associated with poorer recurrence free survival) was explored. Results 91 patients were enrolled and 77 were eligible. CYP2D6 genotype was positively correlated with b, 3m and 6m DMBT (r ranging from 0.457-0. 60 p < 0.001). Both CYP2D6 genotype (r = 0.47; 0.56, p <.0001), and bDM-BT (r=0.60; 0.54; p<.001) were associated with 3m and 6m Endx Css respectively. Seven of 9 patients (78%) with low (≤11.2 nM) 3m Endx Css also had low DM-BT (≤0.9) including 2/2 CYP2D6 PM/PM and 5/5 IM/PM. In contrast, 1 of 48 pts (2%) with a low DM-BT had Endx Css > 11.2 nM. Conclusions In patients not taking potent CYP2D6 inhibitors, DM-BT was associated with CYP2D6 genotype and 3m and 6 m Endx Css but did not provide better discrimination of Endx Css compared to CYP2D6 genotype alone. Further studies are needed to identify additional factors which alter Endx Css. PMID:25714002

  12. Loss of B-cell translocation gene 2 expression in estrogen receptor-positive breast cancer predicts tamoxifen resistance

    PubMed Central

    Takahashi, Maiko; Hayashida, Tetsu; Okazaki, Hiroshi; Miyao, Kazuhiro; Jinno, Hiromitsu; Kitagawa, Yuko

    2014-01-01

    B-cell translocation gene 2 (BTG2), a gene suppressed in a subset of aggressive breast cancer, is repressed by estrogen. BTG2 inhibits the expression of HER ligands and promotes AKT activation, which plays an essential role in the tamoxifen resistance of estrogen receptor (ER)-positive breast cancer. To determine if BTG2 expression modifies tamoxifen efficacy, a cohort of 60 patients treated with adjuvant tamoxifen monotherapy was analyzed. We found that increased BTG2 expression showed better clinical survival and was the only independent prognostic factor for disease-free survival (hazard ratio, 0.691; 95% confidence interval, 0.495–0.963; P = 0.029). Tamoxifen suppressed the human epidermal growth factor receptor 2 (HER2)-Akt signaling in BTG2 expressing ER-positive breast cancer cells with a correlated increase in sensitivity, whereas BTG2 knockdown abrogated this sensitivity. Consistent with this observation, tamoxifen significantly suppressed the growth ratio, tumor weight and Ki-67 expression in BTG2 expressing breast cancer xenografts in mice. These studies demonstrate that BTG2 is a significant factor in tamoxifen response, acting through modification of AKT activation in ER-positive/HER2-negative breast cancer. PMID:24698107

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

    PubMed

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

    2014-11-01

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

  14. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer.

    PubMed

    Vogel, Victor G; Costantino, Joseph P; Wickerham, D Lawrence; Cronin, Walter M; Cecchini, Reena S; Atkins, James N; Bevers, Therese B; Fehrenbacher, Louis; Pajon, Eduardo R; Wade, James L; Robidoux, André; Margolese, Richard G; James, Joan; Runowicz, Carolyn D; Ganz, Patricia A; Reis, Steven E; McCaskill-Stevens, Worta; Ford, Leslie G; Jordan, V Craig; Wolmark, Norman

    2010-06-01

    The selective estrogen-receptor modulator (SERM) tamoxifen became the first U.S. Food and Drug Administration (FDA)-approved agent for reducing breast cancer risk but did not gain wide acceptance for prevention, largely because it increased endometrial cancer and thromboembolic events. The FDA approved the SERM raloxifene for breast cancer risk reduction following its demonstrated effectiveness in preventing invasive breast cancer in the Study of Tamoxifen and Raloxifene (STAR). Raloxifene caused less toxicity (versus tamoxifen), including reduced thromboembolic events and endometrial cancer. In this report, we present an updated analysis with an 81-month median follow-up. STAR women were randomly assigned to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. The risk ratio (RR; raloxifene:tamoxifen) for invasive breast cancer was 1.24 (95% confidence interval [CI], 1.05-1.47) and for noninvasive disease, 1.22 (95% CI, 0.95-1.59). Compared with initial results, the RRs widened for invasive and narrowed for noninvasive breast cancer. Toxicity RRs (raloxifene:tamoxifen) were 0.55 (95% CI, 0.36-0.83; P = 0.003) for endometrial cancer (this difference was not significant in the initial results), 0.19 (95% CI, 0.12-0.29) for uterine hyperplasia, and 0.75 (95% CI, 0.60-0.93) for thromboembolic events. There were no significant mortality differences. Long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease and grew closer over time to tamoxifen in preventing noninvasive disease, with far less toxicity (e.g., highly significantly less endometrial cancer). These results have important public health implications and clarify that both raloxifene and tamoxifen are good preventive choices for postmenopausal women with elevated risk for breast cancer.

  15. Interpreting breast international group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer

    PubMed Central

    2011-01-01

    The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments. Clinicaltrials.gov ID: NCT00004205. PMID:21635709

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

    Cancer.gov

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

  17. Tamoxifen retinopathy.

    PubMed Central

    McKeown, C A; Swartz, M; Blom, J; Maggiano, J M

    1981-01-01

    A 63-year-old female on long-term, high-dose tamoxifen treatment for metastatic breast cancer developed bilateral intraretinal refractile opacities, lesions at the level of the retinal pigment epithelium, and cystoid macular oedema. Images PMID:7225310

  18. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial

    PubMed Central

    Davies, Christina; Pan, Hongchao; Godwin, Jon; Gray, Richard; Arriagada, Rodrigo; Raina, Vinod; Abraham, Mirta; Alencar, Victor Hugo Medeiros; Badran, Atef; Bonfill, Xavier; Bradbury, Joan; Clarke, Michael; Collins, Rory; Davis, Susan R; Delmestri, Antonella; Forbes, John F; Haddad, Peiman; Hou, Ming-Feng; Inbar, Moshe; Khaled, Hussein; Kielanowska, Joanna; Kwan, Wing-Hong; Mathew, Beela S; Müller, Bettina; Nicolucci, Antonio; Peralta, Octavio; Pernas, Fany; Petruzelka, Lubos; Pienkowski, Tadeusz; Rajan, Balakrishnan; Rubach, Maryna T; Tort, Sera; Urrútia, Gerard; Valentini, Miriam; Wang, Yaochen; Peto, Richard

    2013-01-01

    Summary Background For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. Methods In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12 894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. Findings Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·79–1·02] during years 5–9 and 0·75 [0·62–0·90] in later years; breast cancer mortality RR 0·97 [0·79–1·18] during years 5–9 and 0·71 [0·58–0·88] in later years). The cumulative risk of recurrence during years 5–14 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 5–14 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality

  19. Ten Years of Tamoxifen Reduces Breast Cancer Recurrences, Improves Survival

    Cancer.gov

    Taking adjuvant tamoxifen for 10 years after primary treatment leads to a greater reduction in breast cancer recurrences and deaths than taking the drug for only 5 years, according to the results of a large international clinical trial.

  20. ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer.

    PubMed

    Leyland-Jones, Brian; Gray, Kathryn P; Abramovitz, Mark; Bouzyk, Mark; Young, Brandon; Long, Bradley; Kammler, Roswitha; Dell'Orto, Patrizia; Biasi, Maria Olivia; Thürlimann, Beat; Harvey, Vernon; Neven, Patrick; Arnould, Laurent; Maibach, Rudolf; Price, Karen N; Coates, Alan S; Goldhirsch, Aron; Gelber, Richard D; Pagani, Olivia; Viale, Giuseppe; Rae, James M; Regan, Meredith M

    2015-12-01

    Estrogen receptor 1 (ESR1) and ESR2 gene polymorphisms have been associated with endocrine-mediated physiological mechanisms, and inconsistently with breast cancer risk and outcomes, bone mineral density changes, and hot flushes/night sweats. DNA was isolated and genotyped for six ESR1 and two ESR2 single-nucleotide polymorphisms (SNPs) from tumor specimens from 3691 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Associations with recurrence and adverse events (AEs) were assessed using Cox proportional hazards models. 3401 samples were successfully genotyped for five SNPs. ESR1 rs9340799(XbaI) (T>C) variants CC or TC were associated with reduced breast cancer risk (HR = 0.82,95% CI = 0.67-1.0), and ESR1 rs2077647 (T>C) variants CC or TC was associated with reduced distant recurrence risk (HR = 0.69, 95% CI = 0.53-0.90), both regardless of the treatments. No differential treatment effects (letrozole vs. tamoxifen) were observed for the association of outcome with any of the SNPs. Letrozole-treated patients with rs2077647 (T>C) variants CC and TC had a reduced risk of bone AE (HR = 0.75, 95% CI = 0.58-0.98, P interaction = 0.08), whereas patients with rs4986938 (G>A) genotype variants AA and AG had an increased risk of bone AE (HR = 1.37, 95% CI = 1.01-1.84, P interaction = 0.07). We observed that (1) rare ESR1 homozygous polymorphisms were associated with lower recurrence, and (2) ESR1 and ESR2 SNPs were associated with bone AEs in letrozole-treated patients. Genes that are involved in estrogen signaling and synthesis have the potential to affect both breast cancer recurrence and side effects, suggesting that individual treatment strategies can incorporate not only oncogenic drivers but also SNPs related to estrogen activity. PMID:26590813

  1. ESR1 and ESR2 polymorphisms in the BIG 1-98 trial comparing adjuvant letrozole versus tamoxifen or their sequence for early breast cancer.

    PubMed

    Leyland-Jones, Brian; Gray, Kathryn P; Abramovitz, Mark; Bouzyk, Mark; Young, Brandon; Long, Bradley; Kammler, Roswitha; Dell'Orto, Patrizia; Biasi, Maria Olivia; Thürlimann, Beat; Harvey, Vernon; Neven, Patrick; Arnould, Laurent; Maibach, Rudolf; Price, Karen N; Coates, Alan S; Goldhirsch, Aron; Gelber, Richard D; Pagani, Olivia; Viale, Giuseppe; Rae, James M; Regan, Meredith M

    2015-12-01

    Estrogen receptor 1 (ESR1) and ESR2 gene polymorphisms have been associated with endocrine-mediated physiological mechanisms, and inconsistently with breast cancer risk and outcomes, bone mineral density changes, and hot flushes/night sweats. DNA was isolated and genotyped for six ESR1 and two ESR2 single-nucleotide polymorphisms (SNPs) from tumor specimens from 3691 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Associations with recurrence and adverse events (AEs) were assessed using Cox proportional hazards models. 3401 samples were successfully genotyped for five SNPs. ESR1 rs9340799(XbaI) (T>C) variants CC or TC were associated with reduced breast cancer risk (HR = 0.82,95% CI = 0.67-1.0), and ESR1 rs2077647 (T>C) variants CC or TC was associated with reduced distant recurrence risk (HR = 0.69, 95% CI = 0.53-0.90), both regardless of the treatments. No differential treatment effects (letrozole vs. tamoxifen) were observed for the association of outcome with any of the SNPs. Letrozole-treated patients with rs2077647 (T>C) variants CC and TC had a reduced risk of bone AE (HR = 0.75, 95% CI = 0.58-0.98, P interaction = 0.08), whereas patients with rs4986938 (G>A) genotype variants AA and AG had an increased risk of bone AE (HR = 1.37, 95% CI = 1.01-1.84, P interaction = 0.07). We observed that (1) rare ESR1 homozygous polymorphisms were associated with lower recurrence, and (2) ESR1 and ESR2 SNPs were associated with bone AEs in letrozole-treated patients. Genes that are involved in estrogen signaling and synthesis have the potential to affect both breast cancer recurrence and side effects, suggesting that individual treatment strategies can incorporate not only oncogenic drivers but also SNPs related to estrogen activity.

  2. Ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots--development, validation and clinical application during breast cancer adjuvant therapy.

    PubMed

    Antunes, Marina Venzon; Raymundo, Suziane; de Oliveira, Vanessa; Staudt, Dilana Elisabeth; Gössling, Gustavo; Peteffi, Giovana Piva; Biazús, Jorge Villanova; Cavalheiro, José Antônio; Tre-Hardy, Marie; Capron, Arnaud; Haufroid, Vincent; Wallemacq, Pierre; Schwartsmann, Gilberto; Linden, Rafael

    2015-01-01

    A LC-MSMS method for the simultaneous determination of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots samples was developed and validated. The method employs an ultrasound-assisted liquid extraction and a reversed phase separation in an Acquity(®) C18 column (150×2.1 mm, 1.7 µm). Mobile phase was a mixture of formic acid 0.1% (v/v) pH 2.7 and acetonitrile (gradient from 60:40 to 50:50, v/v). Total analytical run time was 8 min. Precision assays showed CV % lower than 10.75% and accuracy in the range 94.5 to 110.3%. Mean analytes recoveries from DBS ranged from 40% to 92%. The method was successfully applied to 91 paired clinical DBS and plasma samples. Dried blood spots concentrations were highly correlated to plasma, with rs>0.83 (P<0.01). Median estimated plasma concentrations after hematocrit and partition factor adjustment were: TAM 123.3 ng mL(-1); NDT 267.9 ng mL(-1), EDF 10.0 ng mL(-1) and HTF 1.3 ng mL(-1,) representing in average 98 to 104% of the actually measured concentrations. The DBS method was able to identify 96% of patients with plasma EDF concentrations below the clinical threshold related to better prognosis (5.9 ng mL(-1)). The procedure has adequate analytical performance and can be an efficient tool to optimize adjuvant breast cancer treatment, especially in resource limited settings. PMID:25476377

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

    PubMed Central

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

    2008-01-01

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

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

    Cancer.gov

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

  5. MicroRNA-320a sensitizes tamoxifen-resistant breast cancer cells to tamoxifen by targeting ARPP-19 and ERRγ.

    PubMed

    Lü, Mingrong; Ding, Keshuo; Zhang, Guofeng; Yin, Mianmian; Yao, Guidong; Tian, Hui; Lian, Jie; Liu, Lin; Liang, Meng; Zhu, Tao; Sun, Fei

    2015-01-01

    Tamoxifen represents a major adjuvant therapy to those patients with estrogen receptor-alpha positive breast cancer. However, tamoxifen resistance occurs quite often, either de novo or acquired during treatment. To investigate the role of miR-320a in the development of resistance to tamoxifen, we established tamoxifen-resistant (TamR) models by continually exposing MCF-7 or T47D breast cancer cells to tamoxifen, and identified microRNA(miRNA)-320a as a down-regulated miRNA in tamoxifen resistant cells. Re-expression of miR-320a was sufficient to sensitize TamR cells to tamoxifen by targeting cAMP-regulated phosphoprotein (ARPP-19) and estrogen-related receptor gamma (ERRγ) as well as their downstream effectors, c-Myc and Cyclin D1. Furthermore, progesterone (P4) promoted the expression of miR-320a by repressing c-Myc expression, while estrogen (E2) exerted the opposite effect. These results suggest the potential therapeutic approach for tamoxifen-resistant breast cancer by restorating miR-320a expression or depleting ARPP-19/ERRγ expression. PMID:25736597

  6. Tamoxifen: catalyst for the change to targeted therapy

    PubMed Central

    Jordan, V. Craig

    2008-01-01

    In the early 1970’s, a failed postcoital contraceptive, ICI 46,474, was reinvented as tamoxifen, the first targeted therapy for breast cancer. A cluster of papers published in the European Journal of Cancer described the idea of targeting tamoxifen to patients with oestrogen receptor positive tumours, and proposed the strategic value of using long-term tamoxifen therapy in an adjuvant setting with a consideration of the antitumour properties of the hydroxylated metabolites of tamoxifen. At the time, these laboratory results were slow to be embraced by the clinical community. Today, it is estimated that hundreds of thousands of breast cancer patients are alive today because of targeted long-term adjuvant tamoxifen therapy. Additionally, the first laboratory studies for the use of tamoxifen as a chemopreventive were published. Eventually, the worth of tamoxifen was tested as a chemopreventive and the drug is now known to have an excellent risk benefit ratio in high risk premenopausal women. Overall, the rigorous investigation of the pharmacology of tamoxifen facilitated tamoxifen’s ubiquitous use for the targeted treatment of breast cancer, chemoprevention and pioneered the exploration of selective estrogen receptor modulators (SERMs). This new concept subsequently heralded the development of raloxifene, a failed breast cancer drug, for the prevention of osteoporosis and breast cancer without the troublesome side effect of endometrial cancer noted in postmenopausal women who take tamoxifen. Currently, the pharmaceutical industry is exploiting the SERM concept for all members of the nuclear receptor superfamily so that medicines can now be developed for diseases once thought impossible. PMID:18068350

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

    PubMed

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

    2014-11-01

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

  8. Tamoxifen regulation of sphingolipid metabolism—therapeutic implications

    PubMed Central

    Morad, Samy A F; Cabot, Myles C

    2015-01-01

    Tamoxifen, a triphenylethylene antiestrogen and one of the first-line endocrine therapies used to treat estrogen receptor-positive breast cancer, has a number of interesting, off-target effects, and among these is the inhibition of sphingolipid metabolism. More specifically, tamoxifen inhibits ceramide glycosylation, and enzymatic step that can adventitiously support the influential tumor-suppressor properties of ceramide, the aliphatic backbone of sphingolipids. Additionally, tamoxifen and metabolites N-desmethyltamoxifen and 4-hydroxytamoxifen, have been shown to inhibit ceramide hydrolysis by the enzyme acid ceramidase. This particular intervention slows ceramide destruction and thereby depresses formation of sphingosine 1-phosphate, a mitogenic sphingolipid with cancer growth-promoting properties. As ceramide-centric therapies are becoming appealing clinical interventions in the treatment of cancer, agents like tamoxifen that can retard the generation of mitogenic sphingolipids and buffer ceramide clearance via inhibition of glycosylation, take on new importance. In this review, we present an abridged, lay introduction to sphingolipid metabolism, briefly chronicle tamoxifen’s history in the clinic, examine studies that demonstrate the impact of triphenylethylenes on sphingolipid metabolism in cancer cells, and canvass works relevant to the use of tamoxifen as adjuvant to drive ceramide-centric therapies in cancer treatment. The objective is to inform the readership of what could be a novel, off-label indication of tamoxifen and structurally-related triphenylethylenes, an indication divorced from estrogen receptor status and one with application in drug resistance. PMID:25964209

  9. Retinoic acid receptor alpha is associated with tamoxifen resistance in breast cancer

    PubMed Central

    Johansson, Henrik J.; Sanchez, Betzabe C.; Mundt, Filip; Forshed, Jenny; Kovacs, Aniko; Panizza, Elena; Hultin-Rosenberg, Lina; Lundgren, Bo; Martens, Ulf; Máthé, Gyöngyvér; Yakhini, Zohar; Helou, Khalil; Krawiec, Kamilla; Kanter, Lena; Hjerpe, Anders; Stål, Olle; Linderholm, Barbro K.; Lehtiö, Janne

    2013-01-01

    About one-third of oestrogen receptor alpha-positive breast cancer patients treated with tamoxifen relapse. Here we identify the nuclear receptor retinoic acid receptor alpha as a marker of tamoxifen resistance. Using quantitative mass spectrometry-based proteomics, we show that retinoic acid receptor alpha protein networks and levels differ in a tamoxifen-sensitive (MCF7) and a tamoxifen-resistant (LCC2) cell line. High intratumoural retinoic acid receptor alpha protein levels also correlate with reduced relapse-free survival in oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen solely. A similar retinoic acid receptor alpha expression pattern is seen in a comparable independent patient cohort. An oestrogen receptor alpha and retinoic acid receptor alpha ligand screening reveals that tamoxifen-resistant LCC2 cells have increased sensitivity to retinoic acid receptor alpha ligands and are less sensitive to oestrogen receptor alpha ligands compared with MCF7 cells. Our data indicate that retinoic acid receptor alpha may be a novel therapeutic target and a predictive factor for oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen. PMID:23868472

  10. Tamoxifen administration to mice.

    PubMed

    Whitfield, Jonathan; Littlewood, Trevor; Soucek, Laura

    2015-03-01

    The strategy of fusing a protein of interest to a hormone-binding domain (HBD) of a steroid hormone receptor allows fine control of the activity of the fused protein. Such fusion proteins are inactive in the absence of ligand, because they are complexed with a variety of intracellular polypeptides. Upon ligand binding, the receptor is released from its inhibitory complex and the fusion protein becomes functional. In the murine estrogen receptor (ER) fusion system, proteins are fused to the HBD of the ER. The system relies on the use of a mutant ER known as ER(TAM). Compared to the wild-type HBD, ER(TAM) has 1000-fold lower affinity for estrogen, yet remains responsive to activation by the synthetic steroid 4-hydroxytamoxifen (4-OHT). Because 4-OHT is expensive, animals can be treated with the cheaper precursor tamoxifen, which is converted into 4-OHT by a liver enzyme. Here we present an overview of the methods used to deliver tamoxifen to mice. The most used method is intraperitoneal injection, because the amount of administered compound can be better controlled, but delivery by oral gavage is also possible. For short-term and immediate-effect studies or when conversion of tamoxifen by the liver is to be avoided, 4-OHT can be used directly. PMID:25734062

  11. A prospective, randomized study on hepatotoxicity of anastrozole compared with tamoxifen in women with breast cancer.

    PubMed

    Lin, Ying; Liu, Jianlun; Zhang, Xiaohua; Li, Li; Hu, Rui; Liu, Jian; Deng, Yongchuan; Chen, Dedian; Zhao, Yangbing; Sun, Shengrong; Ma, Rong; Zhao, Ying; Liu, Jinping; Zhang, Yang; Wang, Xijing; Li, Yafen; He, Pingqing; Li, Enxiao; Xu, Zheli; Wu, Yaqun; Tong, Zhongsheng; Wang, Xiaojia; Huang, Tao; Liang, Zhongxiao; Wang, Shui; Su, Fengxi; Lu, Yunfei; Zhang, Helong; Feng, Guosheng; Wang, Shenming

    2014-09-01

    Tamoxifen and anastrozole are widely used as adjuvant treatment for early stage breast cancer, but their hepatotoxicity is not fully defined. We aimed to compare hepatotoxicity of anastrozole with tamoxifen in the adjuvant setting in postmenopausal breast cancer patients. Three hundred and fifty-three Chinese postmenopausal women with hormone receptor-positive early breast cancer were randomized to anastrozole or tamoxifen after optimal primary therapy. The primary end-point was fatty liver disease, defined as a liver-spleen ratio <0.9 as determined using a computed tomography scan. The secondary end-points included abnormal liver function and treatment failure during the 3-year follow up. The cumulative incidence of fatty liver disease after 3 years was lower in the anastrozole arm than that of tamoxifen (14.6% vs 41.1%, P < 0.0001; relative risk, 0.30; 95% CI, 0.21-0.45). However, there was no difference in the cumulative incidence of abnormal liver function (24.6% vs 24.7%, P = 0.61). Interestingly, a higher treatment failure rate was observed in the tamoxifen arm compared with anastrozole and median times to treatment failure were 15.1 months and 37.1 months, respectively (P < 0.0001; HR, 0.27; 95% CI, 0.20-0.37). The most commonly reported adverse events were 'reproductive system disorders' in the tamoxifen group (17.1%), and 'musculoskeletal disorders' in the anastrozole group (14.6%). Postmenopausal women with hormone receptor-positive breast cancer receiving adjuvant anastrozole displayed less fatty liver disease, suggesting that this drug had a more favorable hepatic safety profile than tamoxifen and may be preferred for patients with potential hepatic dysfunction.

  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

    PubMed Central

    Sun, Zhuoxin; Smith, Ian; Price, Karen N.; Thürlimann, Beat; Ejlertsen, Bent; Bonnefoi, Hervé; Regan, Meredith M.; Goldhirsch, Aron; Coates, Alan S.

    2016-01-01

    Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual 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 with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients. PMID:21892704

  13. 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.

    PubMed

    Chirgwin, Jacquie; Sun, Zhuoxin; Smith, Ian; Price, Karen N; Thürlimann, Beat; Ejlertsen, Bent; Bonnefoi, Hervé; Regan, Meredith M; Goldhirsch, Aron; Coates, Alan S

    2012-01-01

    Letrozole, an aromatase inhibitor, is ineffective in the presence of ovarian estrogen production. Two subpopulations of apparently postmenopausal women might derive reduced benefit from letrozole due to residual or returning ovarian activity: younger women (who have the potential for residual 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 with chemotherapy-induced menopause (HR 0.51 [0.19, 1.39]), the disease-free survival (DFS) point estimate favoring letrozole was marginally more beneficial than in the trial as a whole (HR 0.84 [0.74, 0.95]). Contrary to our initial concern, DFS results for young postmenopausal patients who did not receive chemotherapy and patients with chemotherapy-induced menopause parallel the letrozole benefit seen in the BIG 1-98 population as a whole. These data support the use of letrozole even in such patients.

  14. Evaluation of tamoxifen and metabolites by LC-MS/MS and HPLC methods.

    PubMed

    Heath, D D; Flat, S W; Wu, A H B; Pruitt, M A; Rock, C L

    2014-01-01

    Epidemiological and laboratory evidence suggests that quantification of serum or plasma levels of tamoxifen and its metabolites, 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), Z-4-hydroxytamoxifen (4HT), N-desmethyl-tamoxifen (ND-tam), is a clinically useful tool in the assessment and monitoring of breast cancer status in patients taking adjuvant tamoxifen. A liquid chromatographic mass spectrometric method (LC-MS/MS) was used to measure the blood levels of tamoxifen and its metabolites. This fully automated analytical method is specific, accurate and sensitive. The LC-MS/MS automated technique has now become a widely accepted reference method. This study analysed a randomly selected batch of blood samples from participants enrolled in a breast cancer study to compare results from this reference method in 40 samples with those obtained from a recently developed high-performance liquid chromatography (HPLC) method with fluorescence detection. The mean (SD) concentrations for the LC-MS/MS method (endoxifen 12.6 [7.5] ng/mL, tamoxifen 105 [44] ng/mL, 4-HT 1.9 [1.0] ng/mL, ND-tam 181 [69] ng/mL) and the HPLC method (endoxifen 13.1 [7.8] ng/mL, tamoxifen 108 [55] ng/mL, 4-HT 1.8 [0.8] ng/mL, ND-tam 184 [81] ng/mL) did not show any significant differences. The results confirm that the HPLC method offers an accurate and comparable alternative for the quantification of tamoxifen and tamoxifen metabolites. PMID:24693573

  15. Relationship of PS2 with response to tamoxifen therapy in patients with recurrent breast cancer.

    PubMed Central

    Foekens, J. A.; Portengen, H.; Look, M. P.; van Putten, W. L.; Thirion, B.; Bontenbal, M.; Klijn, J. G.

    1994-01-01

    PS2, an oestrogen-inducible protein, was measured in the cytosol of 230 primary tumours from patients who were subjected to first-line tamoxifen therapy for advanced disease without prior adjuvant therapy with tamoxifen. PS2 correlated positively with oestrogen receptor (ER, P < 0.01) and progesterone receptor content (PgR, P < 0.001), and with the length of progression-free survival (PFS, P = 0.05). Although not statistically significant, higher levels of PS2 (> or = 10 ng mg-1 protein) were also associated with increased probability of response to tamoxifen treatment and a longer total post-relapse survival (PRS). ER, PgR, menopausal status, site of disease and prior adjuvant chemotherapy were all associated with response to tamoxifen therapy and with PFS. In multivariate analysis for PFS, low levels of ER and PgR, visceral metastasis, a disease-free interval of less than 1 year and prior adjuvant chemotherapy were all significantly associated with an increased probability of a rapid disease progression after start of tamoxifen therapy. In the subset of 83 tumours with intermediate levels of ER and PgR (both > or = 10, but not both > or = 75 fmol mg-1 protein), PS2 was positively related with the length of PFS (P < 0.01) and PRS (P < 0.05). PS2 remained the strongest factor in multivariate analysis for PFS (P < 0.01) in this ER/PgR intermediate subgroup, but was not of predictive value in univariate or multivariate analysis for both PFS and PRS in tumours classified as ER/PgR low or high (> or = 75 fmol mg-1 protein). It is concluded that PS2 status may be used as a parameter, additional to ER and PgR, for better refinement of prediction of response to tamoxifen treatment in advanced breast cancer patients especially with intermediate ER/PgR levels in their primary tumour. PMID:7981080

  16. Conversion to eslicarbazepine acetate monotherapy

    PubMed Central

    French, Jacqueline; Jacobson, Mercedes P.; Pazdera, Ladislav; Gough, Mallory; Cheng, Hailong; Grinnell, Todd; Blum, David

    2016-01-01

    Objective: To assess the efficacy and safety of eslicarbazepine acetate (ESL) monotherapy. Methods: This post hoc pooled analysis of 2 randomized double-blind studies (093-045 and -046) included adults with partial-onset seizures medically uncontrolled by 1 or 2 antiepileptic drugs (AEDs). Following the baseline period (8 weeks), eligible patients were randomized 2:1 to receive ESL 1,600 mg or 1,200 mg once daily for 18 weeks; the primary endpoint was study exit by meeting predefined exit criteria (signifying worsening seizure control). In each study, treatment was considered effective if the upper 95% confidence limit for exit rate was lower than the historical control threshold (65.3%). Results: Pooled exit rates were as follows: ESL 1,600 mg = 20.6% (95% confidence interval: 15.6%–26.8%); ESL 1,200 mg = 30.8% (23.0%–40.5%). Use of 2 baseline AEDs or rescue medication, US location, epilepsy duration ≥20 years, and higher maximum baseline seizure frequency were associated with higher exit risks. Median percent reductions in standardized seizure frequency between baseline and the 18-week double-blind period were as follows: ESL 1,600 mg = 43.2%; ESL 1,200 mg = 35.7%; baseline carbamazepine use was associated with smaller reductions. Safety profiles were similar between ESL doses. Conclusions: Exit rates for ESL monotherapy (1,600 mg and 1,200 mg once daily) were lower than the historical control threshold, irrespective of baseline AED use and region, with no additional safety concerns identified. Clinical factors and location clearly influence treatment responses in conversion-to-monotherapy trials. Classification of evidence: This pooled analysis provides Class IV evidence that for adults with medically uncontrolled partial-onset seizures, ESL monotherapy is well tolerated and effective. PMID:26911639

  17. Outcomes of Japanese breast cancer patients treated with pre-operative and post-operative anastrozole or tamoxifen.

    PubMed

    Fujiwara, Yasuhiro; Takatsuka, Yuichi; Imoto, Shigeru; Inaji, Hideo; Ikeda, Tadashi; Akiyama, Futoshi; Tamura, Motoshi; Miyoshi, Kazuya; Iwata, Hiroji; Mitsuyama, Shoshu; Noguchi, Shinzaburo

    2012-03-01

    The present study examined long-term efficacy outcomes in a subgroup of postmenopausal, estrogen receptor-positive Japanese breast cancer patients from the Pre-Operative "Arimidex" Compared with Tamoxifen trial, following pre-operative (3 months) and post-operative (5 years) adjuvant treatment with either anastrozole or tamoxifen. Patients with large, potentially operable, locally-advanced breast cancer were randomized to receive anastrozole (1 mg/day) plus tamoxifen placebo or tamoxifen (20 mg/day) plus anastrozole placebo pre-operatively. After surgery at 3 months, patients continued on the same study medication as adjuvant therapy for up to 5 years or until recurrence, intolerable toxicity or withdrawal of patient consent. Recurrence-free survival and overall survival were measured from the date of randomization to the date of recurrence or death, whichever occurred first. Patients were monitored for adverse events throughout the study period and up to 30 days following administration of the last study medication. During post-operative adjuvant therapy, 4/48 (8%) anastrozole and 25/49 (51%) tamoxifen patients experienced recurrence. There was a significant difference in recurrence-free survival between the two groups (hazard ratio 0.14; 95% confidence interval 0.05-0.41; P = 0.0003). There was a significant increase in overall survival with anastrozole (0.21; 0.05-0.96; P = 0.0436) and there were 2/48 (4%) and 10/49 (20%) deaths with anastrozole and tamoxifen, respectively. Most patients responding to pre-operative therapy remained recurrence-free. Sequential pre-operative/post-operative treatment with anastrozole resulted in lower recurrence and death rates, compared with tamoxifen.

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

    PubMed

    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.

  19. Biorepositories for the Breast Cancer Prevention Trial (BCPT) and the Study of Tamoxifen and Raloxifene (STAR) | Division of Cancer Prevention

    Cancer.gov

    The National Surgical Adjuvant Breast and Bowel Project (NSABP) has a serum and lymphocyte bank with specimens on more than 90% of the 33,000 women in the Breast Cancer Prevention Trial (BCPT) and Study of Tamoxifen and Raloxifene (STAR). They also have tumor blocks on the majority of the breast cancers that have occurred in women on these studies. |

  20. Endometrial carcinoma in breast cancer patients treated with tamoxifen. Two case report and review of the literature.

    PubMed

    Lanza, A; Alba, E; Re, A; Tessarolo, M; Leo, L; Bellino, R; Lauricella, A; Wierdis, T

    1994-01-01

    Recent reports suggest an increased incidence of endometrial cancer in breast cancer patients under long-term adjuvant tamoxifen (TAM) treatment. The Authors describe two cases of endometrial adenocarcinoma among 80 post-menopausal patients affected with breast cancer and treated with TAM. PMID:7875160

  1. Tamoxifen induces a pluripotency signature in breast cancer cells and human tumors.

    PubMed

    Notas, George; Pelekanou, Vassiliki; Kampa, Marilena; Alexakis, Konstantinos; Sfakianakis, Stelios; Laliotis, Aggelos; Askoxilakis, John; Tsentelierou, Eleftheria; Tzardi, Maria; Tsapis, Andreas; Castanas, Elias

    2015-11-01

    Tamoxifen is the treatment of choice in estrogen receptor alpha breast cancer patients that are eligible for adjuvant endocrine therapy. However, ∼50% of ERα-positive tumors exhibit intrinsic or rapidly acquire resistance to endocrine treatment. Unfortunately, prediction of de novo resistance to endocrine therapy and/or assessment of relapse likelihood remain difficult. While several mechanisms regulating the acquisition and the maintenance of endocrine resistance have been reported, there are several aspects of this phenomenon that need to be further elucidated. Altered metabolic fate of tamoxifen within patients and emergence of tamoxifen-resistant clones, driven by evolution of the disease phenotype during treatment, appear as the most compelling hypotheses so far. In addition, tamoxifen was reported to induce pluripotency in breast cancer cell lines, in vitro. In this context, we have performed a whole transcriptome analysis of an ERα-positive (T47D) and a triple-negative breast cancer cell line (MDA-MB-231), exposed to tamoxifen for a short time frame (hours), in order to identify how early pluripotency-related effects of tamoxifen may occur. Our ultimate goal was to identify whether the transcriptional actions of tamoxifen related to induction of pluripotency are mediated through specific ER-dependent or independent mechanisms. We report that even as early as 3 hours after the exposure of breast cancer cells to tamoxifen, a subset of ERα-dependent genes associated with developmental processes and pluripotency are induced and this is accompanied by specific phenotypic changes (expression of pluripotency-related proteins). Furthermore we report an association between the increased expression of pluripotency-related genes in ERα-positive breast cancer tissues samples and disease relapse after tamoxifen therapy. Finally we describe that in a small group of ERα-positive breast cancer patients, with disease relapse after surgery and tamoxifen treatment, ALDH

  2. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: long term results of the Italian Tamoxifen Anastrozole trial.

    PubMed

    Boccardo, F; Guglielmini, P; Bordonaro, R; Fini, A; Massidda, B; Porpiglia, M; Roagna, R; Serra, P; Orzalesi, L; Ucci, G; Rubagotti, A

    2013-05-01

    The Italian Tamoxifen Anastrozole (ITA) trial investigated the efficacy of switching to anastrozole for women who were already on adjuvant tamoxifen since 2-3years. Relapse-free survival (RFS) was the primary end-point; event-free survival (EFS), overall survival (OS) and safety were secondary end-points. Herein, we report an update on the long term results of this trial. At a median follow-up time of 128 months (range 14-168 months), 94 events have been recorded in the tamoxifen group compared with 71 events in the anastrozole group (hazard ratio (HR)=0.71; 95% confidence interval (CI), 0.52-0.97; p=0.03). RFS was also significantly longer in the anastrozole group (HR=0.64; 95% CI, 0.44-0.94; p=0.023); no statistically significant difference between study arms concerning OS was shown, but the trial was not powered enough in respect to this end-point. The incidence of serious adverse events (SAE) like bone fractures was comparable (four in each arm), while gynaecological problems were still significantly more numerous among the women continued on tamoxifen (21 patients developed a SAE in this group, including eight endometrial cancers, compared to three patients who suffered from a SAE, including one endometrial cancer, in the anastrozole group: p<0.000). Present data confirm that switch is safe and can provide long-term gain in terms both of RFS and of EFS, which persists even several years since treatment discontinuation.

  3. Berberine enhances the anti‑tumor activity of tamoxifen in drug‑sensitive MCF‑7 and drug‑resistant MCF‑7/TAM cells.

    PubMed

    Wen, Chunjie; Wu, Lanxiang; Fu, Lijuan; Zhang, Xue; Zhou, Honghao

    2016-09-01

    Berberine, an isoquinoline alkaloid, has been previously demonstrated to possess anti‑breast cancer properties. Tamoxifen is widely used in the prevention and treatment of estrogen receptor-positive breast cancer. Thus, the aim of the present study was to assess whether berberine enhanced the anticancer effect of tamoxifen, and the underlying mechanism involved in this combined effect in tamoxifen-sensitive (MCF-7) and tamoxifen-resistant (MCF-7/TAM) cells using MTS, flow cytometry and western blot assays. The results indicated that berberine demonstrated dose‑ and time‑dependent anti‑proliferative activity in MCF‑7 and MCF‑7/TAM cells. Furthermore, the combination of berberine and tamoxifen induced cell growth inhibition more effectively than tamoxifen alone. The present study also demonstrated that combinational treatment is more effective in inducing G1 phase arrest and activating apoptosis compared tamoxifen alone, which may be due to upregulation of P21 expression and downregulation of the B‑cell CLL/lymphoma 2(Bcl‑2)/Bcl‑2 associated X protein ratio. The results of the present study suggested that berberine may potentially be useful as an adjuvant agent in cancer chemotherapy to enhance the effect of tamoxifen, which will be useful for anti‑tumor therapy and further research.

  4. Berberine enhances the anti‑tumor activity of tamoxifen in drug‑sensitive MCF‑7 and drug‑resistant MCF‑7/TAM cells.

    PubMed

    Wen, Chunjie; Wu, Lanxiang; Fu, Lijuan; Zhang, Xue; Zhou, Honghao

    2016-09-01

    Berberine, an isoquinoline alkaloid, has been previously demonstrated to possess anti‑breast cancer properties. Tamoxifen is widely used in the prevention and treatment of estrogen receptor-positive breast cancer. Thus, the aim of the present study was to assess whether berberine enhanced the anticancer effect of tamoxifen, and the underlying mechanism involved in this combined effect in tamoxifen-sensitive (MCF-7) and tamoxifen-resistant (MCF-7/TAM) cells using MTS, flow cytometry and western blot assays. The results indicated that berberine demonstrated dose‑ and time‑dependent anti‑proliferative activity in MCF‑7 and MCF‑7/TAM cells. Furthermore, the combination of berberine and tamoxifen induced cell growth inhibition more effectively than tamoxifen alone. The present study also demonstrated that combinational treatment is more effective in inducing G1 phase arrest and activating apoptosis compared tamoxifen alone, which may be due to upregulation of P21 expression and downregulation of the B‑cell CLL/lymphoma 2(Bcl‑2)/Bcl‑2 associated X protein ratio. The results of the present study suggested that berberine may potentially be useful as an adjuvant agent in cancer chemotherapy to enhance the effect of tamoxifen, which will be useful for anti‑tumor therapy and further research. PMID:27432642

  5. Tumor-specific HMG-CoA reductase expression in primary premenopausal breast cancer predicts response to tamoxifen

    PubMed Central

    2011-01-01

    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 patients

  6. Leiomyomas in patients receiving Tamoxifen.

    PubMed

    Leo, L; Lanza, A; Re, A; Tessarolo, M; Bellino, R; Lauricella, A; Wierdis, T

    1994-01-01

    In literature there have been only 8 cases of unavoidable laparotomy due to uterine leiomyomas performed in patients with breast cancer on Tamoxifen (TAM). Our article describes two cases of rapidly growing leiomyomas in patients treated with TAM: one of these underwent abdominal hysterectomy while the second stopped taking TAM and began therapy with Triptorelin. This therapeutical alternative could be a useful choice. PMID:8070124

  7. Evaluation of interacellular tamoxifen-induced fluorescence in tamoxifen-resistant human breast adenocarcinoma cells

    NASA Astrophysics Data System (ADS)

    Bachmann, Nathalie; Barberi-Heyob, Muriel; Gramain, Marie-Pierre; Bour, Corinne; Marchal, Sophie; Parache, Robert M.; Guillemin, Francois H.; Merlin, Jean-Louis

    1997-12-01

    A tamoxifen resistant cell line (MCF7TAM) was established from tamoxifen sensitive MCF-7 human adenocarcinoma cells expressing estrogen receptors. The resistant cell line was found to express estrogen receptors to similar level as the parent cell line but the receptors were found to be altered, having lost their ability to bind estradiol or tamoxifen. The fluorescence of eosin-tamoxifen ionic association was used to investigate intracellular location of tamoxifen in both sensitive and resistant cell lines. Fluorescence emission spectra of eosin, tamoxifen and eosin-tamoxifen complex ((lambda) exc equals 480 nm) were analyzed and showed that maximal fluorescence intensity of the complex ((lambda) em equals 540 nm) was four times higher than that of eosin alone while tamoxifen alone did not emit any fluorescence in this spectral range. In MCF-7 cells, tamoxifen was found to be diffusively located in the cytoplasm and nuclear fluorescence intensity was significantly lower. No difference was observed in fluorescence intensity or location in tamoxifen resistant cells, although it has been previously correlated with clinical responsiveness. Improvement of this fluorescence microscopy methodology appears necessary to provide accurate results taking into account the complexity of tamoxifen resistance molecular pathways.

  8. Effective tamoxifen therapy of breast cancer involves both antiproliferative and pro-apoptotic changes.

    PubMed

    Cameron, D A; Keen, J C; Dixon, J M; Bellamy, C; Hanby, A; Anderson, T J; Miller, W R

    2000-05-01

    Despite knowledge of oestrogen receptor status, it is not always possible to predict which breast cancers will respond to tamoxifen. We have previously reported that decreased expression of Bcl-2 and/or Ki-S1 were associated with tumour response to neo-adjuvant tamoxifen in 50 elderly women with oestrogen receptor (ER)-positive breast cancer. In this study, we confirm that the expression of Bcl-2 and Ki-S1 are surrogates for the frequency of apoptosis and mitosis respectively, within these untreated breast cancers, with an inverse relationship between Bcl-2 expression and the apoptotic index (P<0.05), and a positive relationship between Ki-S1 expression and the mitotic index (P<0.01). However, after 3 months' tamoxifen treatment these relationships were no longer apparent. Moreover, amongst the 27 tumours in which Bcl-2 expression was reduced during the 3 months' therapy, there was a significant correlation between the response to therapy and the increase in apoptosis (P<0.05), whereas in those tumours in which Bcl-2 did not fall with therapy, there was a significant correlation between response and the decrease in mitosis (P<0.05). These data suggest there are at least two mechanisms for effective tamoxifen therapy: increased apoptosis as a consequence of reduced Bcl-2 expression, and decreased proliferation. PMID:10785588

  9. Effect of conjoint administration of tamoxifen and high-dose radiation on the development of mammary carcinoma

    SciTech Connect

    Kantorowitz, D.A. ); Thompson, H.J. ); Furmanski, P. )

    1993-04-30

    Tamoxifen is currently advocated for post-menopausal breast cancer patients receiving definitive irradiation after limited surgery. The purpose of this study was to assess in an experimental model for breast cancer whether the efficacy of irradiation is altered by conjoint administration of tamoxifen. To this end, rats with small tumors induced by 1-methyl-1-nitrosourea (MNU) were treated with tamoxifen, radiation, or a combination of the two modalities. Female Sprague Dawley rats were injected i.p. with 50 mg MNU/kg body weight at 50 days of age. At 64 days post carcinogen, the majority of the rats had at least one palpable mammary tumor. At that time radiation with or without tamoxifen treatment was initiated and given 5 days per week for 5 weeks. Radiation dose was 4500 cGy delivered as 25, 180 cGy fractions. Tamoxifen, 500 mg/kg body weight, was administered subcutaneously each day during the irradiation interval. The study was terminated 28 weeks after carcinogen treatment. High dose radiation alone induced a reduction in the size of existing tumors, but resulted in a significant increase in the number of tumors that were detected. Treatment with tamoxifen alone also caused a reduction in tumor volume, but had no effect on final incidence or number of mammary tumors. Combined modality treatment resulted in a significant reduction in the volume of existing tumors and suppressed the enhanced occurrence of additional tumors observed when only radiation alone was administered. The findings of this study indicate that in the context of fractionated, high dose radiation treatment of established mammary cancers, tamoxifen may reduce the likelihood of subsequent tumor development and by so doing prove a helpful simultaneous conjoint adjuvant treatment to post-operative irradiation. 35 refs., 1 fig., 2 tabs.

  10. Adjuvant Endocrine Therapy in Premenopausal Women with Breast Cancer

    PubMed Central

    Kadakia, Kunal C.; Henry, N. Lynn

    2016-01-01

    Breast cancer remains the leading cause of cancer related mortality in premenopausal women. Multiple advances in local and systemic therapies have dramatically improved outcomes in women with HR+ early stage breast cancer. Despite these advances, early and late relapses occur. Therefore multiple adjuvant endocrine therapy trials have been conducted with the goal of decreasing breast cancer recurrence and mortality. Recently, large international trials evaluating extended endocrine therapy as well as ovarian suppression with and without tamoxifen or exemestane have been reported. These studies add to the large body of existing data related to adjuvant endocrine therapy in premenopausal women with breast cancer and provide additional therapeutic options in those at high risk of disease recurrence. This review will synthesize the most recent data and provide an evidenced based approach, highlighting quality-of-life concerns, when considering adjuvant endocrine therapies in premenopausal women. PMID:27058571

  11. Breast cancer chemoprevention: beyond tamoxifen

    PubMed Central

    Fabian, Carol J

    2001-01-01

    A large number of new potential chemoprevention agents are available that target molecular abnormalities found in estrogen receptor (ER)-negative and/or ER-positive precancerous breast tissue and have side effect profiles that differ from tamoxifen. Classes of agents currently undergoing evaluation in clinical prevention trials or those for which testing is planned in the near future include new selective ER modulators, aromatase inactivators/inhibitors, gonadotrophin-releasing hormone agonists, monoterpenes, isoflavones, retinoids, rexinoids, vitamin D derivatives, and inhibitors of tyrosine kinase, cyclooxygenase-2, and polyamine synthesis. New clinical testing models will use morphological and molecular biomarkers to select candidates at highest short-term risk, to predict the response to a particular class of agent, and to assess the response in phase II prevention trials. If validated, morphological and molecular markers could eventually replace cancer incidence as an indicator of efficacy in future phase III trials. PMID:11250754

  12. Tamoxifen-induced hypertriglyceridemia causing acute pancreatitis.

    PubMed

    Singh, Hemant Kumar; Prasad, Mahendranath S; Kandasamy, Arun K; Dharanipragada, Kadambari

    2016-01-01

    Tamoxifen has both antagonistic and agonistic tissue-specific actions. It can have a paradoxical estrogenic effect on lipid metabolism resulting in elevated triglyceride and chylomicron levels. This can cause life-threatening complications like acute pancreatitis. To our knowledge, very few cases of tamoxifen-induced pancreatitis have been reported in the literature. We report a case of severe hypertriglyceridemia and acute pancreatitis following tamoxifen use. A 50-year-old diabetic lady was on tamoxifen (20mg/day) hormonal therapy for breast cancer. Within 3 months of starting therapy, she developed hypertriglyceridemia and acute pancreatitis. Laboratory values include: Serum amylase 778 IU/L, total cholesterol 785 mg/dL, triglycerides 4568 mg/dL and high-density lipoproteins (HDL) 12 mg/dL. Tamoxifen was substituted with letrozole and atorvastatin started. There was a prompt reversal of the adverse effects. Effects on lipid profile must be considered while initiating tamoxifen in predisposed individuals as the consequences are life threatening. PMID:27127396

  13. Tamoxifen OK for Breast Cancer Patients without Uterine Abnormalities

    MedlinePlus

    ... gov/news/fullstory_161118.html Tamoxifen OK for Breast Cancer Patients Without Uterine Abnormalities: Study Pretreatment ultrasounds may ... 2016 (HealthDay News) -- For most women, taking the breast cancer drug tamoxifen doesn't increase their risk of ...

  14. Therapeutic drug monitoring of tamoxifen using LC-MS/MS.

    PubMed

    Tchu, Simone M; Lynch, Kara L; Wu, Alan H B

    2012-01-01

    Tamoxifen is a selective estrogen receptor modulator (SERM) that is used widely in the treatment of estrogen receptor positive breast cancer (ER+). Therapeutic monitoring of tamoxifen, and its metabolites N-desmethyltamoxifen (NDTam) and 4-hydroxy-N-desmethyltamoxifen (endoxifen), may be clinically useful for guiding treatment decisions. Two significant barriers to tamoxifen efficacy are: (1) variability in conversion of tamoxifen into the potent antiestrogenic metabolite, endoxifen, and (2) poor compliance and adherence to tamoxifen therapy. Therapeutic monitoring can be used to address both of these issues. Low levels of endoxifen indicate either poor compliance or poor metabolism of tamoxifen. Low tamoxifen levels would suggest poor compliance while a low ratio of endoxifen to NDTam would be indicative of poor metabolism. Solid phase extraction of patient serum followed by liquid chromatography tandem mass spectrometry (LC-MS/MS) detection enables rapid, accurate, detection of tamoxifen, N-desmethyltamoxifen, and endoxifen. PMID:22767121

  15. Tamoxifen Resistance: Emerging Molecular Targets.

    PubMed

    Rondón-Lagos, Milena; Villegas, Victoria E; Rangel, Nelson; Sánchez, Magda Carolina; Zaphiropoulos, Peter G

    2016-01-01

    17β-Estradiol (E2) plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM) or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM's biological activity could provide the necessary framework to understand the complex effects of this drug in target cells. Moreover, this could explain, at least in part, the development of resistance and indicate an optimal therapeutic option. This review highlights the implications of TAM in breast cancer as well as the role of receptors/signal pathways recently suggested to be involved in the development of TAM resistance. G protein-coupled estrogen receptor, Androgen Receptor and Hedgehog signaling pathways are emerging as novel therapeutic targets and prognostic indicators for breast cancer, based on their ability to mediate estrogenic signaling in ERα-positive or -negative breast cancer. PMID:27548161

  16. Tamoxifen Resistance: Emerging Molecular Targets

    PubMed Central

    Rondón-Lagos, Milena; Villegas, Victoria E.; Rangel, Nelson; Sánchez, Magda Carolina; Zaphiropoulos, Peter G.

    2016-01-01

    17β-Estradiol (E2) plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM) or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM’s biological activity could provide the necessary framework to understand the complex effects of this drug in target cells. Moreover, this could explain, at least in part, the development of resistance and indicate an optimal therapeutic option. This review highlights the implications of TAM in breast cancer as well as the role of receptors/signal pathways recently suggested to be involved in the development of TAM resistance. G protein—coupled estrogen receptor, Androgen Receptor and Hedgehog signaling pathways are emerging as novel therapeutic targets and prognostic indicators for breast cancer, based on their ability to mediate estrogenic signaling in ERα-positive or -negative breast cancer. PMID:27548161

  17. CYP2D6 and UGT2B7 Genotype and Risk of Recurrence in Tamoxifen-Treated Breast Cancer Patients

    PubMed Central

    Drury, Suzy; Hayes, Daniel F.; Stearns, Vered; Thibert, Jacklyn N.; Haynes, Ben P.; Salter, Janine; Sestak, Ivana; Cuzick, Jack; Dowsett, Mitch

    2012-01-01

    Background Adjuvant tamoxifen therapy substantially decreases the risk of recurrence and mortality in women with hormone (estrogen and/or progesterone) receptor–positive breast cancer. Previous studies have suggested that metabolic conversion of tamoxifen to endoxifen by cytochrome P450 2D6 (CYP2D6) is required for patient benefit from tamoxifen therapy. Methods Tumor specimens from a subset of postmenopausal patients with hormone receptor–positive early-stage (stages I, II, and IIIA) breast cancer, who were enrolled in the randomized double-blind Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial, were genotyped for variants in CYP2D6 (N = 1203 patients: anastrozole [trade name: Arimidex] group, n = 615 patients; tamoxifen group, n = 588 patients) and UDP-glucuronosyltransferase-2B7 (UGT2B7), whose gene product inactivates endoxifen (N = 1209 patients; anastrozole group, n = 606 patients; tamoxifen group, n = 603 patients). Genotyping was performed using polymerase chain reaction–based TaqMan assays. Based on the genotypes for CYP2D6, patients were classified as poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM) phenotypes. We evaluated the association of CYP2D6 and UGT2B7 genotype with distant recurrence (primary endpoint) and any recurrence (secondary endpoint) by estimating the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) using Cox proportional hazards models. All statistical tests were two-sided. Results After a median follow-up of 10 years, no statistically significant associations were observed between CYP2D6 genotype and recurrence in tamoxifen-treated patients (PM vs EM: HR for distant recurrence = 1.25, 95% CI = 0.55 to 3.15, P = .64; HR for any recurrence = 0.99, 95% CI = 0.48 to 2.08, P = .99). A near-null association was observed between UGT2B7 genotype and recurrence in tamoxifen-treated patients. No associations were observed between CYP2D6 and UGT2B7 genotypes and

  18. Use of adjuvants in the treatment of Acinetobacter baumannii.

    PubMed

    Pachón-Ibáñez, María Eugenia; Smani, Younes; Pachón, Jerónimo

    2016-01-01

    The current antibiotic crisis to treat infections by Acinetobacter baumannii is linked with the increase of antimicrobial resistance and the lack of development of new antimicrobial drugs. For this reason, new alternatives for the treatment and control of infections by A. baumannii are necessary. Several studies have reported the effect of adjuvants to restore the efficacy of existing antimicrobial agents. Herein, we analyzed the main results on the development of adjuvant drugs, as monotherapy or in combination therapy with existing antimicrobial agents, which have shown promising results in vitro and in vivo. However, caution is needed and further extensive in vivo studies have to be performed to confirm the potential use of these adjuvants as true therapeutic alternatives. PMID:26620637

  19. [Tamoxifen and cervico-vaginal cytology].

    PubMed

    Ayoubi, J M; Monrozies, X; Ayoubi, F; Charasson, T; Reme, J M

    1994-04-01

    The impact of tamoxifen on the genital tract was assessed by cervico-vaginal cytology. Fifty two post-menopausal patients treated with tamoxifen for breast cancer were regularly monitored, with a pre-treatment reference smear showing a profoundly menopausal status, followed by an anual smear. Smears returned to a functional status in 44% of patients after 2 to 5 years treatment. The agonist effect of tamoxifen appears to be beyond any doubt, and responsible for certain adverse reactions. This should not bring into question the usefulness of the drug, but indicates the need for regular monitoring and, in the presence of a functional smear, further investigation by vaginal ultrasonography is essential in order to evaluate the status of the endometrium. PMID:8036383

  20. Efficacy and Safety of Switching Latanoprost Monotherapy to Bimatoprost Monotherapy or Combination of Brinzolamide and Latanoprost

    PubMed Central

    Imasawa, Mitsuhiro; Tanabe, Joji; Kashiwagi, Fumiko; Kashiwagi, Kenji

    2016-01-01

    Purpose: To prospectively assess the efficacy and safety of switching to bimatoprost monotherapy or brinzolamide and latanoprost combination therapy in patients who had been receiving latanoprost monotherapy. Methods: A prospective, open-label study was conducted. Patients with primary open-angle glaucoma or ocular hypertension who had been receiving latanoprost monotherapy for three months or more were enrolled. Bimatoprost was substituted for latanoprost in one eye (BIM group), and brinzolamide was added to the latanoprost in the other eye (BRZ group) simultaneously. The patients underwent examinations at 6 weeks (visit 1) and 12 weeks (visit 2) after changing therapies. Subsequently, the treatments were returned to latanoprost monotherapy. The patients underwent another examination 6 weeks (visit 3) after the return to latanoprost. The parameters examined were intraocular pressure (IOP), conjunctival hyperemia, and corneal epithelial damage. Results: Twenty-six patients (13 men and 13 women) completed the protocol. Both groups showed a significant IOP reduction at visits 1 and 2 compared with the baseline, with a similar magnitude (BIM group: P = 0.016 at visit 1, P = 0.025 at visit 2, BRZ group: P = 0.0006 at visit 1, P = 0.028 at visit 2). The IOPs at the baseline and on visit 3 were similar in both groups (P = 0.7). The two groups showed no changes in either conjunctival hyperemia or corneal epithelial damage compared with the baseline. Conclusion: Bimatoprost monotherapy and brinzolamide adjunctive to latanoprost similarly reduced the IOP, with no additive adverse effects, compared with latanoprost monotherapy. PMID:27073587

  1. Vibrational study of tamoxifen citrate polymorphism

    NASA Astrophysics Data System (ADS)

    Gamberini, M. C.; Baraldi, C.; Tinti, A.; Palazzoli, F.; Ferioli, V.

    2007-09-01

    The trans isomer of ( Z)-2-[ p-(1,2-diphenyl-butenyl)phenoxy]- N, N-dimethyletylamine (tamoxifen) is well known for its endocrine activity as an antiestrogenic agent. Its citrate salt, a widely used pharmaceutical agent, appears in three main polymorphic forms, two of which are well known (I and II) and another form not yet well evidenced. A vibrational study has been conducted for identifying the two known polymorphic forms of tamoxifen citrate (I and II) and for characterising the other form (form III) examined in this study. Other techniques for the characterization of the different polymorphs, such as XRDP, have been used.

  2. 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

    PubMed Central

    Rabaglio, M.; Sun, Z.; Castiglione-Gertsch, M.; Hawle, H.; Thürlimann, B.; Mouridsen, H.; Campone, M.; Forbes, J. F.; Paridaens, R. J.; Colleoni, M.; Pienkowski, T.; Nogaret, J.-M.; Láng, I.; Smith, I.; Gelber, R. D.; Goldhirsch, A.; Coates, A. S.

    2009-01-01

    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 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 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 fracture, and previous hormone replacement therapy. Conclusions: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients. PMID:19474112

  3. Oxidative stress contributes to the tamoxifen-induced killing of breast cancer cells: implications for tamoxifen therapy and resistance

    PubMed Central

    Bekele, Raie T.; Venkatraman, Ganesh; Liu, Rong-Zong; Tang, Xiaoyun; Mi, Si; Benesch, Matthew G. K.; Mackey, John R.; Godbout, Roseline; Curtis, Jonathan M.; McMullen, Todd P. W.; Brindley, David N.

    2016-01-01

    Tamoxifen is the accepted therapy for patients with estrogen receptor-α (ERα)-positive breast cancer. However, clinical resistance to tamoxifen, as demonstrated by recurrence or progression on therapy, is frequent and precedes death from metastases. To improve breast cancer treatment it is vital to understand the mechanisms that result in tamoxifen resistance. This study shows that concentrations of tamoxifen and its metabolites, which accumulate in tumors of patients, killed both ERα-positive and ERα-negative breast cancer cells. This depended on oxidative damage and anti-oxidants rescued the cancer cells from tamoxifen-induced apoptosis. Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE). This increased the transcription of anti-oxidant genes and multidrug resistance transporters. As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage. These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice. Additionally, high levels of expression of Nrf2, ABCC1, ABCC3 plus NAD(P)H dehydrogenase quinone-1 in breast tumors of patients at the time of diagnosis were prognostic of poor survival after tamoxifen therapy. Therefore, overcoming tamoxifen-induced activation of the ARE could increase the efficacy of tamoxifen in treating breast cancer. PMID:26883574

  4. Second non-breast primary cancer following adjuvant therapy for early breast cancer: A report from the International Breast Cancer Study Group

    PubMed Central

    Gianni, Lorenzo; Gelber, Shari; Ravaioli, Alberto; Price, Karen N.; Panzini, Ilaria; Fantini, Manuela; Castiglione-Gertsch, Monica; Pagani, Olivia; Simoncini, Edda; Gelber, Richard D.; Coates, Alan S.; Goldhirsch, Aron

    2009-01-01

    The incidence of second non-breast primary cancer following adjuvant treatment was evaluated using data from patients enrolled from 1978 to 1999 in four International Breast Cancer Study Group (IBCSG) trials. The occurrence of these tumours as sites of first failure was assessed separately for two treatment comparisons: toremifene versus tamoxifen for five years in 1035 patients in IBCSG Trials 12-93 and 14-93 with a median follow-up of eight years and endocrine therapy (toremifene or tamoxifen) versus chemoendocrine therapy (CMF or AC plus toremifene or tamoxifen) in 1731 patients from IBCSG Trials III, VII and 12-93, with a combined median follow-up of 14 years. No significant differences in second non-breast primary tumours were observed in either comparison. In particular the incidences of second primary uterine tumours with toremifene and tamoxifen were similar and no significant increase of secondary leukaemias was observed with chemoendocrine therapy compared with endocrine therapy. PMID:19062268

  5. Differential efficacy of three cycles of CMF followed by tamoxifen in patients with ER-positive and ER-negative tumors: Long-term follow up on IBCSG Trial IX

    PubMed Central

    Aebi, S.; Sun, Z.; Braun, D.; Castiglione-Gertsch, M.; Rabaglio, M.; Gelber, R. D.; Crivellari, D.; Lindtner, J.; Snyder, R.; Karlsson, P.; Simoncini, E.; Gusterson, B. A.; Viale, G.; Regan, M. M.; Coates, A. S.; Goldhirsch, A.

    2011-01-01

    Background: The benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed. Patients and methods: After stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of ‘classical’ CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMF→tamoxifen) or to tamoxifen alone for 5 years. Results: ERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMF→tamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER-positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes. Conclusion: CMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER-positive tumors who may benefit from adjuvant chemotherapy. PMID:21282282

  6. [Menstrual abnormality in patients with breast cancer receiving adjuvant endocrine-chemotherapy].

    PubMed

    Yasumura, T; Oka, T; Honjo, H; Okada, H

    1988-10-01

    Menstrual status and ovarian function were studied in 24 premenopausal breast cancer patients receiving adjuvant therapy with chemotherapy and tamoxifen or chemotherapy alone. In 13 of 24 patients (54.1%), abnormal menses, including amenorrhea in 12 cases and oligomenorrhea in 1 case, developed during adjuvant therapy. In patients with abnormal menses, serum estradiol was significantly lower, and the levels of gonadotropins were significantly higher than in patients with normal menses. Among 13 patients with abnormal menses, 4 patients treated with cyclophosphamide revealed persistent amenorrhea during the whole period with adjuvant therapy, and the levels of serum estradiol and progesterone were extremely low. Furthermore, in these patients normal menses has not recovered and the levels of serum estradiol and progesterone remained low 4 to 5 months after cessation of cyclophosphamide administration. Thus, adjuvant chemotherapy caused depression of ovarian function, and cyclophosphamide induced ovarian failure, resulting in complete amenorrhea.

  7. Perinatal induction of Cre recombination with tamoxifen.

    PubMed

    Lizen, Benoit; Claus, Melissa; Jeannotte, Lucie; Rijli, Filippo M; Gofflot, Françoise

    2015-12-01

    Temporal control of site-specific recombination is commonly achieved by using a tamoxifen-inducible form of Cre or Flp recombinases. Although powerful protocols of induction have been developed for gene inactivation at adult stages or during embryonic development, induction of recombination at late gestational or early postnatal stages is still difficult to achieve. In this context, using the ubiquitous CMV-CreER(T2) transgenic mice, we have tested and validated two procedures to achieve recombination just before and just after birth. The efficiency of recombination was evaluated in the brain, which is known to be more problematic to target. For the late gestation treatment with tamoxifen, different protocols of complementary administration of progesterone and estrogen were tested. However, delayed delivery and/or mortality of pups due to difficult delivery were always observed. To circumvent this problem, pups were collected from tamoxifen-treated pregnant dams by caesarian section at E18.5 and given to foster mothers. For postnatal treatment, different dosages of tamoxifen were administered by intragastric injection to the pups during 3 or 4 days after birth. The efficiency of these treatments was analyzed at P7 using a transgenic reporter line. They were also validated with the Hoxa5 conditional allele. In conclusion, we have developed efficient procedures that allow achieving efficient recombination of floxed alleles at perinatal stages. These protocols will allow investigating the late/adult functions of many developmental genes, whose characterization has been so far restricted to embryonic development. PMID:26395370

  8. Tamoxifen through GPER upregulates aromatase expression: a novel mechanism sustaining tamoxifen-resistant breast cancer cell growth.

    PubMed

    Catalano, Stefania; Giordano, Cinzia; Panza, Salvatore; Chemi, Francesca; Bonofiglio, Daniela; Lanzino, Marilena; Rizza, Pietro; Romeo, Francesco; Fuqua, Suzanne A W; Maggiolini, Marcello; Andò, Sebastiano; Barone, Ines

    2014-07-01

    Tamoxifen resistance is a major clinical challenge in breast cancer treatment. Aromatase inhibitors are effective in women who progressed or recurred on tamoxifen, suggesting a role of local estrogen production by aromatase in driving tamoxifen-resistant phenotype. However, the link between aromatase activity and tamoxifen resistance has not yet been reported. We investigated whether long-term tamoxifen exposure may affect aromatase activity and/or expression, which may then sustain tamoxifen-resistant breast cancer cell growth. We employed MCF-7 breast cancer cells, tamoxifen-resistant MCF-7 cells (MCF-7 TR1 and TR2), SKBR-3 breast cancer cells, cancer-associated fibroblasts (CAFs1 and CAFs2). We used tritiated-water release assay, realtime-RT-PCR, and immunoblotting analysis for evaluating aromatase activity and expression; anchorage-independent assays for growth; reporter-gene, electrophoretic-mobility-shift, and chromatin-immunoprecipitation assays for promoter activity studies. We demonstrated an increased aromatase activity and expression, which supports proliferation in tamoxifen-resistant breast cancer cells. This is mediated by the G-protein-coupled receptor GPR30/GPER, since knocking-down GPER expression or treatment with a GPER antagonist reversed the enhanced aromatase levels induced by long-term tamoxifen exposure. The molecular mechanism was investigated in ER-negative, GPER/aromatase-positive SKBR3 cells, in which tamoxifen acts as a GPER agonist. Tamoxifen treatment increased aromatase promoter activity through an enhanced recruitment of c-fos/c-jun complex to AP-1 responsive elements located within the promoter region. As tamoxifen via GPER induced aromatase expression also in CAFs, this pathway may be involved in promoting aggressive behavior of breast tumors in response to tamoxifen treatment. Blocking estrogen production and/or GPER signaling activation may represent a valid option to overcome tamoxifen-resistance in breast cancers.

  9. [Influenza vaccine and adjuvant].

    PubMed

    Nakayama, Tetsuo

    2011-01-01

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

  10. Tamoxifen Induces Apoptosis of Leishmania major Promastigotes in Vitro

    PubMed Central

    Doroodgar, Masoud; Delavari, Mahdi; Doroodgar, Moein; Abbasi, Ali; Taherian, Ali Akbar; Doroodgar, Abbas

    2016-01-01

    Tamoxifen is an antagonist of the estrogen receptor and currently used for the treatment of breast cancer. The current treatment of cutaneous leishmaniasis with pentavalent antimony compounds is not satisfactory. Therefore, in this study, due to its antileishmanial activity, effects of tamoxifen on the growth of promastigotes and amastigotes of Leishmania major Iranian strain were evaluated in vitro. Promastigotes and amastigotes were treated with different concentrations (1, 5, 10, 20, and 50 μg/ml) and time periods (24, 48, and 72 hr) of tamoxifen. After tamoxifen treatment, MTT assay (3-[4,5-dimethylthiazol-2-yl]-2,5 biphenyl tetrazolium bromide assay) was used to determine the percentage of live parasites and Graph Pad Prism software to calculate IC50. Flow cytometry was applied to investigate the induction of tamoxifen-induced apoptosis in promastigotes. The half maximal inhibitory concentration (IC50) of tamoxifen on promastigotes was 2.6 μg/ml after 24 hr treatment. Flow cytometry analysis showed that tamoxifen induced early and late apoptosis in Leishmania promastigotes. While after 48 hr in control group the apoptosis was 2.0%, the 50 µg/L concentration of tamoxifen increased it to 59.7%. Based on the in vitro antileishmanial effect, tamoxifen might be used for leishmaniasis treatment; however, further researches on in vivo effects of tamoxifen in animal models are needed. PMID:26951973

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

    PubMed

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

    2014-11-01

    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-induced liver carcinogenesis may be associated with its ability to induce genotoxic alterations only without affecting the cellular epigenome and an inability of tamoxifen to induce the development of NAFLD.

  12. Oncologic Outcome of Radical Prostatectomy as Monotherapy for Men with High-risk Prostate Cancer

    PubMed Central

    Furukawa, Junya; Miyake, Hideaki; Inoue, Taka-aki; Ogawa, Takayoshi; Tanaka, Hirokazu; Fujisawa, Masato

    2016-01-01

    Background The objective of this study was to review our experience with radical prostatectomy (RP) as monotherapy for men with high-risk prostate cancer (PCa). Patients and Methods This study included 382 consecutive patients who were diagnosed with high-risk PCa according to the D'Amico definition and subsequently underwent RP without neoadjuvant therapy. Biochemical recurrence (BR) was defined as a serum prostate-specific antigen (PSA) level ≥ 0.2 ng/ml on two consecutive measurements, and none of the patients received any adjuvant therapies until their serum PSA levels reached ≥ 0.4 ng/ml. Results The median preoperative serum PSA level in these 382 patients was 15.9 ng/ml. Pathological stages ≥ pT2c and Gleason scores ≥ 8 were observed in 288 and 194 patients, respectively. During the observation period (median, 48.0 months), BR occurred in 134 patients, and the 5-year BR-free survival rate was 60.1%; however, no patient died of cancer progression. Multivariate analysis identified capsular invasion, seminal vesicle invasion, and surgical margin status as independent predictors of BR. Conclusions Comparatively favorable cancer control could be achieved using RP as monotherapy for men with high-risk PCa; however, RP alone may be insufficient for patients with capsular invasion, seminal vesicle invasion, and/or surgical margin positivity. PMID:27390578

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

    Cancer.gov

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

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

    PubMed

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

    2011-10-01

    Tamoxifen is a known anti-cancer drug and established estrogen receptor modulator. Few clinical studies have earlier implicated the drug in thrombotic complications attributable to lower anti-thrombin and protein S levels in plasma. However, action of tamoxifen on platelet signalling machinery has not been elucidated in detail. In the present report we show that tamoxifen is endowed with significant inhibitory property against human platelet aggregation. From a series of in vivo and in vitro studies tamoxifen was found to inhibit almost all platelet functions, prolong tail bleeding time in mouse and profoundly prevent thrombus formation at injured arterial wall in mice, as well as on collagen matrix perfused with platelet-rich plasma under arterial shear against the vehicle dimethylsulfoxide (DMSO). These findings strongly suggest that tamoxifen significantly downregulates platelet responses and holds potential as a promising anti-platelet/anti-thrombotic agent. PMID:21866300

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

    PubMed

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

    2011-10-01

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

  16. Tamoxifen Action in ER-Negative Breast Cancer

    PubMed Central

    Manna, Subrata; Holz, Marina K.

    2016-01-01

    Breast cancer is a highly heterogeneous disease. Tamoxifen is a selective estrogen receptor (ER) modulator and is mainly indicated for the treatment of breast cancer in postmenopausal women and postsurgery neoadjuvant therapy in ER-positive breast cancers. Interestingly, 5–10% of the ER-negative breast cancers have also shown sensitivity to tamoxifen treatment. The involvement of molecular markers and/or signaling pathways independent of ER signaling has been implicated in tamoxifen sensitivity in the ER-negative subgroup. Studies reveal that variation in the expression of estrogen-related receptor alpha, ER subtype beta, tumor microenvironment, and epigenetics affects tamoxifen sensitivity. This review discusses the background of the research on the action of tamoxifen that may inspire future studies to explore effective therapeutic strategies for the treatment of ER-negative and triple-negative breast cancers, the latter being an aggressive disease with worse clinical outcome. PMID:26989346

  17. Phase III Study Comparing Exemestane With Tamoxifen As First-Line Hormonal Treatment of Metastatic Breast Cancer in Postmenopausal Women: The European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group

    PubMed Central

    Paridaens, Robert J.; Dirix, Luc Y.; Beex, Louk V.; Nooij, Marianne; Cameron, David A.; Cufer, Tanja; Piccart, Martine J.; Bogaerts, Jan; Therasse, Patrick

    2008-01-01

    Purpose This phase III randomized open-label clinical trial was designed to evaluate the efficacy and safety of the steroidal aromatase inactivator exemestane versus the antiestrogen tamoxifen as first-line treatment for metastatic breast cancer (MBC) in postmenopausal women. Patients and Methods The study was conducted at 81 centers and enrolled postmenopausal patients with measurable hormone-sensitive metastatic or locally advanced breast cancer. Prior adjuvant chemotherapy and/or tamoxifen were allowed. One previous chemotherapy regimen and no prior hormone therapy for advanced disease were permitted. Patients were randomly assigned to receive exemestane 25 mg or tamoxifen 20 mg orally once daily until disease progression or unacceptable toxicity occurred. Results A total of 371 patients enrolled at 79 sites (182 exemestane, 189 tamoxifen) were included in the analysis. Both treatments were generally well tolerated without major toxicity. Overall response rate was greater for exemestane than for tamoxifen treatment (46% v 31%; odds ratio = 1.85; 95% CI, 1.21 to 2.82; P = .005). Median progression-free survival (PFS) was longer with exemestane (9.9 months; 95% CI, 8.7 to 11.8 months) than with tamoxifen (5.8 months; 95% CI, 5.3 to 8.1 months). However, these early differences (Wilcoxon P = .028) did not translate to a longer-term benefit in PFS, the primary study end point (log-rank P = .121). There was also no difference in survival between both study arms. Conclusion Exemestane is an effective and well-tolerated first-line hormonal treatment for postmenopausal women with MBC and offers significant early improvement in time to tumor progression when compared with tamoxifen. PMID:18794551

  18. Mechanisms of Action of Adjuvants

    PubMed Central

    Awate, Sunita; Babiuk, Lorne A.; Mutwiri, George

    2013-01-01

    Adjuvants are used in many vaccines, but their mechanisms of action are not fully understood. Studies from the past decade on adjuvant mechanisms are slowly revealing the secrets of adjuvant activity. In this review, we have summarized the recent progress in our understanding of the mechanisms of action of adjuvants. Adjuvants may act by a combination of various mechanisms including formation of depot, induction of cytokines and chemokines, recruitment of immune cells, enhancement of antigen uptake and presentation, and promoting antigen transport to draining lymph nodes. It appears that adjuvants activate innate immune responses to create a local immuno-competent environment at the injection site. Depending on the type of innate responses activated, adjuvants can alter the quality and quantity of adaptive immune responses. Understanding the mechanisms of action of adjuvants will provide critical information on how innate immunity influences the development of adaptive immunity, help in rational design of vaccines against various diseases, and can inform on adjuvant safety. PMID:23720661

  19. Suitability of tamoxifen-induced mutagenesis for behavioral phenotyping.

    PubMed

    Vogt, M A; Chourbaji, S; Brandwein, C; Dormann, C; Sprengel, R; Gass, P

    2008-05-01

    Tamoxifen-induced mutagenesis via the so-called CreER(T2) fusion enzyme is a key technology for the inducible gene knockout in the adult murine brain. However, it requires a subchronic transient treatment with high doses of the non-selective estrogen receptor antagonist tamoxifen. It has been shown earlier that acute tamoxifen treatment causes behavioral alterations, while the long-term behavioral effects of tamoxifen in mice are so far unknown. Therefore C57BL/6 male mice, a common strain used for targeted mutagenesis and behavioral analyses, were subjected to a tamoxifen treatment protocol as used for inducible mutagenesis in vivo, and analyzed for effects on general behavior (locomotion, exploration), emotional behavior (anxiety, depression) and on learning and memory after a drug-free interval period of 4 weeks. The results demonstrate that a test for depression-like behavior, i.e. the Forced Swim Test, is affected even more than 4 weeks after tamoxifen treatment. In contrast, in all other tests, tamoxifen treated mice showed unaltered behaviors, indicating that the currently established 5-day protocol of tamoxifen treatment (40 mg/kg bid) for inducible mutagenesis has no or little effects on the behavior of C57BL/6 male mice after a latency period of 4 weeks. These results are important for all studies using tamoxifen-induced mutagenesis since this protocol obviously does not evoke alterations in general behaviors such as locomotion, exploration or anxiety-like behaviors, which might confound more complex behavioral analyses, nor does it affect standard tests for learning and memory, such as Morris Water Maze, contextual and cued Fear Conditioning and T-Maze learning.

  20. Adjuvant chemo- and hormonal therapy in locally advanced breast cancer: a randomized clinical study

    SciTech Connect

    Schaake-Koning, C.; van der Linden, E.H.; Hart, G.; Engelsman, E.

    1985-10-01

    Between 1977 and 1980, 118 breast cancer patients with locally advanced disease, T3B-4, any N, M0 or T1-3, tumor positive axillary apex biopsy, were randomized to one of three arms: I: radiotherapy (RT) to the breast and adjacent lymph node areas; II: RT followed by 12 cycles of cyclophosphamide, methotrexate, 5 fluorouracil (CMF) and tamoxifen during the chemotherapy period; III: 2 cycles of adriamycin and vincristine (AV), alternated with 2 cycles of CMF, then RT, followed by another 4 cycles of AV, alternated with 4 CMF; tamoxifen during the entire treatment period. The median follow-up period was 5 1/2 years. The adjuvant chemo- and hormonal therapy did not improve the overall survival; the 5-year survival was 37% for all three treatment arms. There was no statistically significant difference in RFS between the three modalities, nor when arm I was compared to arm II and III together. LR was not statistically different over the three treatment arms. In 18 of the 24 patients with LR, distant metastases appeared within a few months from the local recurrence. The menopausal status did not influence the treatment results. Dose reduction in more than 4 cycles of chemotherapy was accompanied by better results. In conclusion: adjuvant chemo- and hormonal therapy did not improve RFS and overall survival. These findings do not support the routine use of adjuvant chemo- and endocrine therapy for inoperable breast cancer.

  1. Modern Vaccine Adjuvant/Formulation—Session 9: Adjuvants

    PubMed Central

    Dalençon, François

    2013-01-01

    The Session 9 of the Modern Vaccine Adjuvant/Formulation meeting pointed out the permanent need for vaccine improvement and for adjuvant development. Indeed, the increasing use of recombinant subunit vaccines for both parenteral and mucosal vaccination necessitates the development of improved adjuvants. This session dealt with strategies for the development of new vaccine adjuvants with respect to the availability of new molecules targeting specifically the receptors of the systemic or mucosal immune system. PMID:23938771

  2. Vaccines, adjuvants and autoimmunity.

    PubMed

    Guimarães, Luísa Eça; Baker, Britain; Perricone, Carlo; Shoenfeld, Yehuda

    2015-10-01

    Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future.

  3. Ten Years of Tamoxifen Reduces Breast Cancer Recurrences, Improves Survival

    MedlinePlus

    ... Cancer Screening Research Ten Years of Tamoxifen Reduces Breast Cancer Recurrences, Improves Survival For some women with breast ... took it for 5 years. (See the table.) Breast Cancer Recurrence and Death 5 to 14 Years after ...

  4. Tamoxifen and depression: drug interactions in breast cancer.

    PubMed

    McMichael, Katherine S; Adams, Katie; Breden Crouse, Ericka L

    2013-09-01

    This case describes a 76-year-old African-American female with a history of depression, breast cancer, and hypothyroidism admitted to the inpatient geriatric psychiatry unit for an electroconvulsive therapy (ECT) evaluation. She had one previous episode of depression, which began after a lumpectomy in 2007. Her home medication regimen included tamoxifen 20 mg daily. This case highlights the incidence of depression in persons with breast cancer, examines the controversy of tamoxifen-induced depression, and evaluates antidepressant considerations regarding potentially efficacy-reducing cytochrome P450 2D6 drug interactions with tamoxifen. The pharmacy team played an active role in educating the medical team regarding tamoxifen drug interactions. After many discussions, the patient was ultimately treated with mirtazapine 15 mg at bedtime, in addition to ECT. PMID:24007891

  5. More Evidence Tamoxifen, Other Meds Help Limit Breast Cancer's Spread

    MedlinePlus

    ... html More Evidence Tamoxifen, Other Meds Help Limit Breast Cancer's Spread 6-year study finds follow-up therapy ... class of drugs called aromatase inhibitors does cut breast cancer patients' risk of developing cancer in their other ...

  6. Individualized Tamoxifen Dose Escalation: Confirmation of Feasibility, Question of Utility.

    PubMed

    Hertz, Daniel L; Rae, James M

    2016-07-01

    Tamoxifen may require metabolic activation to endoxifen for efficacy in treating hormone receptor-positive breast cancer. Dose escalation in patients with low endoxifen concentrations could enhance treatment efficacy. This approach is clinically feasible, and successfully increases endoxifen concentrations; however, it is unknown whether patients benefit from individualized tamoxifen dose escalation. Clin Cancer Res; 22(13); 3121-3. ©2016 AACRSee related article by Fox et al., p. 3164.

  7. Individualized Tamoxifen Dose Escalation: Confirmation of Feasibility, Question of Utility.

    PubMed

    Hertz, Daniel L; Rae, James M

    2016-07-01

    Tamoxifen may require metabolic activation to endoxifen for efficacy in treating hormone receptor-positive breast cancer. Dose escalation in patients with low endoxifen concentrations could enhance treatment efficacy. This approach is clinically feasible, and successfully increases endoxifen concentrations; however, it is unknown whether patients benefit from individualized tamoxifen dose escalation. Clin Cancer Res; 22(13); 3121-3. ©2016 AACRSee related article by Fox et al., p. 3164. PMID:27012810

  8. Tamoxifen experimental carcinogenicity studies: Implications for human effects

    SciTech Connect

    Williams, G.M.

    1995-02-01

    Tamoxifen is an effective antiestrogen in the treatment of breast cancer and is considered highly safe. In recent years, several trials have been initiated in women to evaluate its potential for the prevention of breast cancer. Such long-term administration of a medication to healthy people requires a substantial degree of safety. This review examines experimental carcinogenicity and mechanistic studies on tamoxifen and the implications for human effects. 25 refs.

  9. Leishmania is not prone to develop resistance to tamoxifen.

    PubMed

    Coelho, Adriano C; Trinconi, Cristiana T; Senra, Luisa; Yokoyama-Yasunaka, Jenicer K U; Uliana, Silvia R B

    2015-12-01

    Tamoxifen, an antineoplastic agent, is active in vitro and in vivo against the parasitic protozoa Leishmania. As part of our efforts to unravel this drug's mechanisms of action against the parasite and understand how resistance could arise, we tried to select tamoxifen-resistant Leishmania amazonensis. Three different strategies to generate tamoxifen resistant mutants were used: stepwise increase in drug concentration applied to promastigote cultures, chemical mutagenesis followed by drug selection and treatment of infected mice followed by selection of amastigotes. For amastigote selection, we employed a method with direct plating of parasites recovered from lesions into semi-solid media. Tamoxifen resistant parasites were not rescued by any of these methods. Miltefosine was used as a control in selection experiments and both stepwise selection and chemical mutagenesis allowed successful isolation of miltefosine resistant mutants. These findings are consistent with a multi-target mode of action to explain tamoxifen's leishmanicidal properties. Considering that drug resistance is a major concern in anti-parasitic chemotherapy, these findings support the proposition of using tamoxifen as a partner in drug combination schemes for the treatment of leishmaniasis.

  10. Laser vaccine adjuvants

    PubMed Central

    Kashiwagi, Satoshi; Brauns, Timothy; Gelfand, Jeffrey; Poznansky, Mark C

    2014-01-01

    Immunologic adjuvants are essential for current vaccines to maximize their efficacy. Unfortunately, few have been found to be sufficiently effective and safe for regulatory authorities to permit their use in vaccines for humans and none have been approved for use with intradermal vaccines. The development of new adjuvants with the potential to be both efficacious and safe constitutes a significant need in modern vaccine practice. The use of non-damaging laser light represents a markedly different approach to enhancing immune responses to a vaccine antigen, particularly with intradermal vaccination. This approach, which was initially explored in Russia and further developed in the US, appears to significantly improve responses to both prophylactic and therapeutic vaccines administered to the laser-exposed tissue, particularly the skin. Although different types of lasers have been used for this purpose and the precise molecular mechanism(s) of action remain unknown, several approaches appear to modulate dendritic cell trafficking and/or activation at the irradiation site via the release of specific signaling molecules from epithelial cells. The most recent study, performed by the authors of this review, utilized a continuous wave near-infrared laser that may open the path for the development of a safe, effective, low-cost, simple-to-use laser vaccine adjuvant that could be used in lieu of conventional adjuvants, particularly with intradermal vaccines. In this review, we summarize the initial Russian studies that have given rise to this approach and comment upon recent advances in the use of non-tissue damaging lasers as novel physical adjuvants for vaccines. PMID:25424797

  11. Evolution of endocrine adjuvant therapy for early breast cancer.

    PubMed

    Lønning, Per Eystein

    2010-04-01

    Endocrine treatment plays a pivotal role in the adjuvant therapy of patients harbouring oestrogen and/or progesterone receptor positive breast cancer. The objective of this paper is to critically review endocrine treatment options in early breast cancer focusing on ongoing development. Literature was collected through the ISI Web of Science and PubMed in January/February 2009 with subsequent update by December 2009, using the words breast cancer, endocrine therapy, oestrogen receptor and aromatase. Endocrine therapy improves outcome in early breast cancer. Yet several controversies remain. There has recently been a lack of general consensus regarding the limit of oestrogen receptor positivity. As for adjuvant therapy in general and use of aromatase inhibitors in particular, we need the results from ongoing studies to decide what may be the optimal duration of therapy and regimen (sequential treatment versus monotherapy; one drug compared with another). Further, there is a need to critically assess optimal use of endocrine therapy for metastatic disease among patients previously exposed to endocrine regimens in the adjuvant setting. While in general the mechanisms of resistance to endocrine therapy among ER positive tumours remains unknown, merging evidence suggest a role of different growth factor pathways, in particular HER-2 activation. Thus, particular attention is paid to the topic of HER-2 expression as a potential cause of endocrine resistance.

  12. Biomarkers and outcome after tamoxifen treatment in node-positive breast cancers from elderly women

    PubMed Central

    Daidone, M G; Luisi, A; Martelli, G; Benini, E; Veneroni, S; Tomasic, G; De Palo, G; Silvestrini, R

    2000-01-01

    The predictive role of tumour proliferative rate and expression of p53, bcl-2 and bax proteins, alone and in association with tumour size, nodal involvement and oestrogen receptors (ER), was analysed on 145 elderly patients (≥70 years of age) with histologically assessed node-positive breast cancers treated with radical or conservative surgery plus radiotherapy followed by adjuvant tamoxifen for at least 1 year. The 7-year probability of relapse was significantly higher for patients with tumours rapidly proliferating (hazard ratio (HR) = 2.0, P = 0.01), overexpressing p53 (HR = 4.4, P = 0.0001), weakly or not exhibiting bcl-2 (HR = 1.9, P = 0.02), without ERs (HR = 3.4, P = 0.0001) or with ≥ 4 positive lymph nodes (HR = 2.3, P = 0.003) than for patients with tumours expressing the opposite patho-biological profile. Conversely, tumour size and bax expression failed to influence relapse-free survival. Adjustment for the duration of tamoxifen treatment did not change these findings. Oestrogen receptors, cell proliferation, p53 accumulation and bcl-2 expression were also predictive for overall survival. Within ER-positive tumours, cell proliferation, p53 accumulation, bcl-2 expression and lymph node involvement provided significant and independent information for relapse and, in association, identified subgroups of patients with relapse probabilities of 20% (low-risk group, exhibiting only one unfavourable factor) to 90% (high-risk group, exhibiting three unfavourable factors). Such data could represent the initial framework for a biologically tailored therapy even for elderly patients and highlight the importance of a patho-biological characterization of their breast cancers. © 2000 Cancer Research Campaign PMID:10646876

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

    PubMed

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

    2014-11-01

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

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

    PubMed

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

    1994-01-01

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

  15. p53 status dictates responses of B lymphomas to monotherapy with proteasome inhibitors

    PubMed Central

    Yu, Duonan; Carroll, Martin

    2007-01-01

    The proapoptotic function of p53 is thought to underlie most anticancer modalities and is also activated in response to oncogenic insults, such as overexpression of the Myc oncoprotein. Here we generated tractable B lymphomas using retroviral transduction of the MYC oncogene into hematopoietic cells with 2 knock-in alleles encoding a fusion between p53 and 4-hydroxytamoxifen (4OHT) receptor (p53ERTAM). In these polyclonal tumors, Myc is the only oncogenic lesion, and p53ERTAM status can be rapidly toggled between “off” and “on” with 4OHT, provided that the Trp53 promoter has been independently activated. Although 4OHT can trigger widespread apoptosis and overt tumor regression even in the absence of DNA-damaging agents, in tumors with high levels of Mdm2 these responses are blunted. However, cotreatment with proteasome inhibitors fully restores therapeutic effects in vivo. Similarly, human Burkitt lymphomas with wild-type p53 and overexpression of Hdm2 are highly sensitive to proteasome inhibitors, unless p53 levels are reduced using the HPV-E6 ubiquitin ligase. Therefore, proteasome inhibitors could be highly effective as a monotherapy against Myc-induced lymphomas, with no need for adjuvant chemotherapy or radiation therapy. On the other hand, their efficacy is crucially dependent on the wild-type p53 status of the tumor, placing important restrictions on patient selection. PMID:17284530

  16. Adjuvants for allergy vaccines.

    PubMed

    Moingeon, Philippe

    2012-10-01

    Allergen-specific immunotherapy is currently performed via either the subcutaneous or sublingual routes as a treatment for type I (IgE dependent) allergies. Aluminum hydroxide or calcium phosphate are broadly used as adjuvants for subcutaneous allergy vaccines, whereas commercial sublingual vaccines rely upon high doses of aqueous allergen extracts in the absence of any immunopotentiator. Adjuvants to be included in the future in products for allergen specific immunotherapy should ideally enhance Th1 and CD4+ regulatory T cell responses. Imunomodulators impacting dendritic or T cell functions to induce IL10, IL12 and IFNγ production are being investigated in preclinical allergy models. Such candidate adjuvants encompass synthetic or biological immunopotentiators such as glucocorticoids, 1,25-dihydroxy vitamin D3, selected probiotic strains (e.g., Lactobacillus and Bifidobacterium species) as well as TLR2 (Pam3CSK4), TLR4 (monophosphoryl lipid A, synthetic lipid A analogs) or TLR9 (CpGs) ligands. Furthermore, the use of vector systems such as mucoadhesive particules, virus-like particles or liposomes are being considered to enhance allergen uptake by tolerogenic antigen presenting cells present in mucosal tissues.

  17. Vaccine Potentiation by Combination Adjuvants

    PubMed Central

    Levast, Benoît; Awate, Sunita; Babiuk, Lorne; Mutwiri, George; Gerdts, Volker; van Drunen Littel-van den Hurk, Sylvia

    2014-01-01

    Adjuvants are crucial components of vaccines. They significantly improve vaccine efficacy by modulating, enhancing, or extending the immune response and at the same time reducing the amount of antigen needed. In contrast to previously licensed adjuvants, current successful adjuvant formulations often consist of several molecules, that when combined, act synergistically by activating a variety of immune mechanisms. These “combination adjuvants” are already registered with several vaccines, both in humans and animals, and novel combination adjuvants are in the pipeline. With improved knowledge of the type of immune responses needed to successfully induce disease protection by vaccination, combination adjuvants are particularly suited to not only enhance, but also direct the immune responses desired to be either Th1-, Th2- or Th17-biased. Indeed, in view of the variety of disease and population targets for vaccine development, a panel of adjuvants will be needed to address different disease targets and populations. Here, we will review well-known and new combination adjuvants already licensed or currently in development—including ISCOMs, liposomes, Adjuvant Systems Montanides, and triple adjuvant combinations—and summarize their performance in preclinical and clinical trials. Several of these combination adjuvants are promising having promoted improved and balanced immune responses. PMID:26344621

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

    PubMed

    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. PMID:26690777

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

    PubMed

    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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

    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. Potential implications of adjuvant endocrine therapy for the oral health of postmenopausal women with breast cancer

    PubMed Central

    Taichman, L. Susan; Havens, Aaron M.

    2012-01-01

    Current adjuvant treatment modalities for breast cancer that express the estrogen receptor or progesterone receptor include adjuvant anti-estrogen therapies, and tamoxifen and aromatase inhibitors. Bone, including the jaw, is an endocrine-sensitive organ, as are other oral structures. This review examines the potential links between adjuvant anti-estrogen treatments in postmenopausal women with hormone receptor positive breast cancer and oral health. A search of PubMed, EMBASE, CENTRAL, and the Web of Knowledge was conducted using combinations of key terms “breast,” “cancer,” “neoplasm,” “Tamoxifen,” “Aromatase Inhibitor,” “chemotherapy,” “hormone therapy,” “alveolar bone loss,” “postmenopausal bone loss,” “estrogen,” “SERM,” “hormone replacement therapy,” and “quality of life.” We selected articles published in peer-reviewed journals in the English. The authors found no studies reporting on periodontal diseases, alveolar bone loss, oral health, or oral health-related quality of life in association with anti-estrogen breast cancer treatments in postmenopausal women. Periodontal diseases, alveolar bone density, tooth loss, and conditions of the soft tissues of the mouth have all been associated with menopausal status supporting the hypothesis that the soft tissues and bone of the oral cavity could be negatively affected by anti-estrogen therapy. As a conclusion, the impact of adjuvant endocrine breast cancer therapy on the oral health of postmenopausal women is undefined. The structures of the oral cavity are influenced by estrogen; therefore, anti-estrogen therapies may carry the risk of oral toxicities. Oral health care for breast cancer patients is an important but understudied aspect of cancer survivorship. PMID:22986813

  3. [Tamoxifen treatment and pulmunary embolism: a case report and literature review].

    PubMed

    Zanini, Gregoriana; Fontanella, Benedetta; Racheli, Marco; Bortolotti, Monica; Pasini, Gian Franco

    2013-03-01

    Breast carcinoma is becoming a spread disease that needs a specif teraphy. Tamoxifen is the first line treatment in patients with positivity of expression of estrogen receptors. The risk of thromboembolism is high in patients treated with tamoxifene indipendent from the neoplastic disease. This work focuses the attention on tamoxifen mechanism of thrombosis.

  4. Cyclodextrin-based nanosponges: effective nanocarrier for tamoxifen delivery.

    PubMed

    Torne, Satyen; Darandale, Sharad; Vavia, Pradeep; Trotta, Francesco; Cavalli, Roberta

    2013-01-01

    The purpose of the present study was to develop Tamoxifen loaded β-cyclodextrin nanosponges for oral drug delivery. The three types of Tamoxifen loaded β-cyclodextrin nanosponges were synthesized by varying the molar ratios of β-cyclodextrin to carbonyldiimidazole as a crosslinker viz. 1:2, 1:4 and 1:8. The Tamoxifen nanosponge complex (TNC) with particle size of 400-600 nm was obtained by freeze drying method. Differential scanning calorimetry, Fourier transformed infra-red spectroscopy and X-ray powder diffraction studies confirmed the complexation of Tamoxifen with cyclodextrin nanosponge. AUC and Cmax of TNC formulation (1236.4 ± 16.12 µg · mL(-1) h, 421.156 ± 0.91 µg/mL) after gastric intubation were 1.44 fold and 1.38 fold higher than plain drug (856.079 ± 15.18 µg · mL(-1) h, 298.532 ± 1.15 µg/mL). Cytotoxic studies on MCF-7 cells showed that TNC formulation was more cytotoxic than plain Tamoxifen after 24 and 48 h of incubation. PMID:22235935

  5. Effects of Exemestane and Tamoxifen treatment on bone texture analysis assessed by TBS in comparison with bone mineral density assessed by DXA in women with breast cancer.

    PubMed

    Kalder, Matthias; Hans, Didier; Kyvernitakis, Ioannis; Lamy, Olivier; Bauer, Martina; Hadji, Peyman

    2014-01-01

    We performed an analysis of a substudy of the randomized Tamoxifen Exemestane Adjuvant Multinational trial to determine the effects of exemestane (EXE) and tamoxifen (TAM) adjuvant treatment on bone mineral density (BMD) measured by dual-energy X-ray absorptiometry compared with the trabecular bone score, a novel grey-level texture measurement that correlates with 3-dimensional parameters of bone texture in postmenopausal women with hormone receptor-positive breast cancer for the first time. In total, 36 women were randomized to receive TAM (n = 17) or EXE (n = 19). Patients receiving TAM showed a mean increase of BMD in lumbar spine from baseline of 1.0%, 1.5%, and 1.9% and in trabecular bone score of 2.2%, 3.5%, and 3.3% at 6-, 12-, and 24-mo treatment, respectively. Conversely, patients receiving EXE showed a mean decrease from baseline in lumbar spine BMD of -2.3%, -3.6%, and -5.3% and in trabecular bone score of -0.9%, -1.7%, and -2.3% at 6-, 12-, and 24-mo treatment, respectively. Changes in trabecular bone score from baseline at spine were also significantly different between EXE and TAM: p = 0.05, 0.007, and 0.006 at 6, 12, and 24 mo, respectively. TAM induced an increase in BMD and bone texture analysis, whereas EXE resulted in decreases. The results were independent from each other.

  6. Assessment of vascular effects of tamoxifen and its metabolites on the rat perfused hindquarter vascular bed.

    PubMed

    Montenegro, Marcelo F; Pessa, Lisandra R; Gomes, Valéria A; Desta, Zeruesenay; Flockhart, David A; Tanus-Santos, Jose E

    2009-05-01

    Tamoxifen has been suggested to produce beneficial cardiovascular effects, although the mechanisms for these effects are not fully known. Moreover, although tamoxifen metabolites may exhibit 30-100 times higher potency than the parent drug, no previous study has compared the effects produced by tamoxifen and its metabolites on vascular function. Here, we assessed the vascular responses to acetylcholine and sodium nitroprusside on perfused hindquarter vascular bed of rats treated with tamoxifen or its main metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen, and endoxifen) for 2 weeks. Plasma and whole-blood thiobarbituric acid reactive substances (TBARS) concentrations were determined using a fluorometric method. Plasma nitrite and NOx (nitrite + nitrate) concentrations were determined using an ozone-based chemiluminescence assay and Griess reaction, respectively. Treatment with tamoxifen reduced the responses to acetylcholine (pD(2) = 2.2 +/- 0.06 and 1.9 +/- 0.05 after vehicle and tamoxifen, respectively; P < 0.05), while its metabolites improved these responses (pD(2) = 2.5 +/- 0.04 after N-desmethyl-tamoxifen, 2.5 +/- 0.03 after 4-hydroxy-tamoxifen, and 2.6 +/- 0.08 after endoxifen; P < 0.01). Tamoxifen and its metabolites showed no effect on endothelial-independent responses to sodium nitroprusside (P > 0.05). While tamoxifen treatment resulted in significantly higher plasma and whole blood lipid peroxide levels (37% and 62%, respectively; both P < 0.05), its metabolites significantly decreased lipid peroxide levels (by approximately 50%; P < 0.05). While treatment with tamoxifen decreased the concentrations of markers of nitric oxide formation by approximately 50% (P < 0.05), tamoxifen metabolites had no effect on these parameters (P > 0.05). These results suggest that while tamoxifen produces detrimental effects, its metabolites produce counteracting beneficial effects on the vascular system and on nitric oxide/reactive oxygen species formation. PMID

  7. Luteinizing hormone-releasing hormone analogues--the rationale for adjuvant use in premenopausal women with early breast cancer.

    PubMed

    Jonat, W

    1998-09-01

    Current standard adjuvant therapies for early breast cancer include tamoxifen and chemotherapy, depending on the disease prognosis and menopausal status. Luteinizing hormone-releasing hormone (LHRH) analogues offer a different approach to the management of early breast cancer in pre- and perimenopausal women. The most widely studied LHRH analogue is goserelin. It acts on the hypothalamic-pituitary axis to suppress ovarian function, decreasing luteinizing hormone and oestradiol levels to post-menopausal values. Pooled data from 228 premenopausal and perimenopausal patients with advanced breast cancer enrolled in 29 studies worldwide demonstrated an objective response rate for goserelin, 3.6 mg, of 36.4%, with a median duration of response of 44 weeks. These results fall well within the ranges of reported response rates for ovarian ablation and for tamoxifen in similar patient populations. By virtue of its mode of action, goserelin does not stimulate the ovaries and is unlikely to have detrimental effects on the endometrium. In addition, given that goserelin has no oestrogen agonist-like effects, unlike tamoxifen, there is no potential for tumour stimulation in those patients becoming resistant to treatment. Goserelin is generally well tolerated, and the main side-effects are related to ovarian suppression, which is potentially reversible. Preliminary results in premenopausal women with early breast cancer indicate that endocrine treatment with goserelin plus tamoxifen may be as effective as standard combination chemotherapy (cyclophosphamide-methotrexate-5-fluorouracil), but has significantly less acute toxicity. A number of large, randomized trials are now in progress to assess the potential role of goserelin as adjuvant therapy for early breast cancer.

  8. Response of patients with indolent systemic mastocytosis to tamoxifen citrate.

    PubMed

    Butterfield, Joseph H; Chen, Dong

    2016-01-01

    We examined whether tamoxifen citrate at 20mg/day for 1 year had a beneficial effect on laboratory findings, bone marrow mastocytosis, common clinical symptoms, or quality-of-life assessment for 5 women and 2 men with indolent systemic mastocytosis. Tamoxifen was well tolerated. We found significant reductions in the platelet count, serum alkaline phosphatase, and 24-h urinary excretion of N-methylhistamine and significant increases in serum lactate dehydrogenase and (excluding 2 patients taking aspirin) in 24-h urinary excretion of 11β-prostaglandin F2α. Overall, no change occurred in percent involvement of bone marrow by mastocytosis. Symptom scores were mild and did not change during the treatment. The 36-Item Short Form Health Survey scores for quality of life physical and mental components showed no marked changes. Tamoxifen, an older, nonhematotoxic medication, has limited activity in systemic mastocytosis at the dosage used in this study.

  9. Paraovarian cystic endosalpingiosis in association with tamoxifen therapy

    PubMed Central

    McCluggage, W; Weir, P

    2000-01-01

    This report describes a case of macroscopically visible cystic endosalpingiosis involving the paraovarian region in a woman who had been taking tamoxifen for breast cancer. A 2.5 cm multicystic lesion was seen on the external surface of the right ovary and histological examination showed a mass of dilated glands lined by ciliated tubal-type epithelium and set in a fibrovascular stroma. Cystic endosalpingiosis resulting in a tumour-like mass is a rarely described entity which is probably not well recognised by histopathologists. Although unlikely to be mistaken for malignancy, the lesion may result in diagnostic confusion. The role of tamoxifen in the development of the lesion in the present case is not clear but the oestrogenic effects of this drug may have contributed to its formation. Key Words: ovary • paraovarian region • endosalpingiosis, tamoxifen PMID:10767837

  10. Retreating recurrent breast cancer with the same CMF-containing regimen used as adjuvant therapy. The International Breast Cancer Study Group.

    PubMed

    Castiglione-Gertsch, M; Tattersall, M; Hacking, A; Goldhirsch, A; Gudgeon, A; Gelber, R D; Lindtner, J; Coates, A; Collins, J; Isley, M; Senn, H J; Rudenstam, C M

    1997-12-01

    Breast cancer metastases appearing soon after adjuvant chemotherapy (within 12 months of its completion) are usually resistant to retreatment with the same cytotoxic agents, while relapses occurring later (beyond 12 months) regress when rechallenged with the same agents, showing similar response rates observed in non-pretreated patients with advanced disease. The International Breast Cancer Study Group (IBCSG) prospectively explored the efficacy of retreatment for patients upon relapse using the same therapy administered during the adjuvant programme. 87 patients previously treated with an adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil) combination chemotherapy (with or without the addition of low-dose prednisone and tamoxifen), who had measurable first breast cancer relapse, usually after at least 6 months of completion of the adjuvant treatment, were treated with CMF. Pretreatment consisted of 1-3 CMF courses in 27 patients and 4 or more courses in 60 patients. 17 patients were retreated with additional tamoxifen or had tamoxifen stopped at relapse. The data of these patients are shown separately. 47 of the 86 fully evaluable patients (55%) had an objective response, which was complete in 25 (29%). The dominant metastatic type and the number of involved sites were the most important factors influencing response to retreatment. Patients with soft tissue metastases had a high response rate (36/52, 69%) compared with those who had visceral involvement (9/24, 38%) or those with bony disease (2/10, 20%) (P = 0.002). In conclusion, response rates to retreatment with CMF were similar to those expected in a non-pretreated population. The patterns of relapse and the number of metastatic sites were the most important factors predicting response to retreatment, while treatment-free interval (usually longer than 6 months due to the study design) did not influence response rates. This study supports the hypothetic effectiveness of late reintroduction of adjuvant

  11. Ongoing HIV replication in cerebrospinal fluid under successful monotherapy.

    PubMed

    Bierhoff, Marieke; Boucher, Charles A B; Fibriani, Azzania; Ten Kate, Reinier W

    2013-01-01

    We report a case of an HIV-infected patient who was successfully treated with ritonavir/lopinavir (r/LPV) monotherapy for several years. He presented with neurological symptoms and high HIV RNA levels in cerebrospinal fluid (CSF). Sequencing of the HIV from the CSF revealed mutations in the protease gene reflecting resistance against most protease inhibitors, that is, lopinavir and ritonavir. His regimen was switched and after 2 months the HIV RNA viral load was again undetectable in both plasma as well as in CSF. Monotherapy with r/LPV may not be sufficient to fully suppress viral replication in the central nervous system in all individuals and may lead to compartimentalization and the selection of resistant mutations of HIV in the central nervous system. PMID:23344463

  12. Pharmacokinetics and bioavailability of tamoxifen in postmenopausal healthy women.

    PubMed

    Fuchs, W S; Leary, W P; van der Meer, M J; Gay, S; Witschital, K; von Nieciecki, A

    1996-04-01

    A randomised cross-over study in 24 postmenopausal women was selected to establish bioequivalence of two tamoxifen (CAS 10540-29-1) formulations. In addition, this study compiled pharmacokinetic parameters for the current 30 mg regimen in postmenopausal women, the target population of tamoxifen therapy. Mean Cmax values of 59.1 +/- 8.9 (T) and 63.6 +/0 11.1 (R) ng/ml were attained 3.6 +/- 1.2 (T) and 3.2 +/- 1.1 (R) h after administration of 30 mg tamoxifen for the test (T) and the reference (R) formulation. The mean AUC (0-480) of tamoxifen was calculated as 3299.7 +/- 761.2 (T) and 3370.1 +/- 701.9 (R) ng x h/ml. The corresponding AUC (0-480) of the active metabolite, N-desmethyl-tamoxifen, exceeded that of the parent drug with 4359.7 +/- 830.5 (T) and 4306.3 +/- 835.2 (R) ng x h/ml, whereas maximal concentrations of the metabolite were distinctly decreased with 14.4 +/- 3.3 (T) and 14.3 +/- 2.4 (R) ng/ml. The pharmacokinetic parameters evaluated in this study are well in line with already known pharmacokinetic data generated with young male volunteers and postmenopausal patients with breast cancer. Precise analytics and an extremely long blood sampling period facilitated an accurate determination of tamoxifen's half-life in postmenopausal women with 210.1 +/- 60.8 (T) and 209.8 +/- 59.9 (R) h. Based on the extremely long half-life, the suitability of a cross-over design is discussed and recommended for further studies.

  13. [Monotherapy of ureteral calculi with extracorporeal shockwave lithotripsy].

    PubMed

    Robles, J E; de Castro, F; Isa, W A; Rosell, D; Agüera, L G; Sánchez, P L; Zudaire, J J; Berián, J M

    1992-05-01

    We reviewed our experience with ESWL in the treatment of 401 patients with ureteral stones in order to evaluate if a higher disintegration and clearance rates could be achieved without prior manipulation of ureteral calculi, i.e., ESWL used as "in situ" monotherapy. The global stone free rate were 83%, 85% and 91% at 15 days, 1 month and 3 months after ESWL. We also analyzed the results according to the efficiency quotient (EQ).

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

    PubMed Central

    Sensorn, Insee; Sukasem, Chonlaphat; Sirachainan, Ekaphop; Chamnanphon, Montri; Pasomsub, Ekawat; Trachu, Narumol; Supavilai, Porntip; Pinthong, Darawan; Wongwaisayawan, Sansanee

    2016-01-01

    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=0.004; hazard ratio [HR] =3.05; 95% confidence interval [CI], 1.44–6.47). In the multivariate analysis, tumor size >5 cm remained predictive of distant metastasis (P<0.001; HR=5.49; 95% CI, 2.30–13.10). ABCC2 −24CC were shown to be associated with increased risk of distant metastasis (P=0.040; adjusted HR=2.34; 95% CI, 1.04–5.27). The combined genotype of ABCC2 −24CC − ABCB1 3435 CT+TT was associated with increased risk of distant and bone metastasis (P=0.020; adjusted HR=2.46; 95% CI, 1.15–5.26 and P=0.040; adjusted HR=3.70; 95% CI, 1.06–12.89, respectively). Conclusion This study indicates that polymorphisms of ABCC2 and ABCB1 are independently associated with bone metastasis. Further prospective studies with larger sample sizes are needed to verify this finding. PMID:27110128

  15. Carbohydrate-based immune adjuvants

    PubMed Central

    Petrovsky, Nikolai; Cooper, Peter D

    2011-01-01

    The role for adjuvants in human vaccines has been a matter of vigorous scientific debate, with the field hindered by the fact that for over 80 years, aluminum salts were the only adjuvants approved for human use. To this day, alum-based adjuvants, alone or combined with additional immune activators, remain the only adjuvants approved for use in the USA. This situation has not been helped by the fact that the mechanism of action of most adjuvants has been poorly understood. A relative lack of resources and funding for adjuvant development has only helped to maintain alum’s relative monopoly. To seriously challenge alum’s supremacy a new adjuvant has many major hurdles to overcome, not least being alum’s simplicity, tolerability, safety record and minimal cost. Carbohydrate structures play critical roles in immune system function and carbohydrates also have the virtue of a strong safety and tolerability record. A number of carbohydrate compounds from plant, bacterial, yeast and synthetic sources have emerged as promising vaccine adjuvant candidates. Carbohydrates are readily biodegradable and therefore unlikely to cause problems of long-term tissue deposits seen with alum adjuvants. Above all, the Holy Grail of human adjuvant development is to identify a compound that combines potent vaccine enhancement with maximum tolerability and safety. This has proved to be a tough challenge for many adjuvant contenders. Nevertheless, carbohydrate-based compounds have many favorable properties that could place them in a unique position to challenge alum’s monopoly over human vaccine usage. PMID:21506649

  16. Comparative Uterotrophic Effects of Endoxifen and Tamoxifen in Ovariectomized Sprague Dawley Rats

    PubMed Central

    Schweikart, Karen M.; Eldridge, Sandy R.; Safgren, Stephanie L.; Parman, Toufan; Reid, Joel M.; Ames, Matthew M.; Goetz, Matthew P.; Davis, Myrtle A.

    2014-01-01

    Endoxifen (4-hydroxyl-N-desmethyl tamoxifen), one of the major active metabolites of tamoxifen, has substantially greater estrogen antagonist properties and antiproliferative effects in breast tumor cells than tamoxifen, a mixed estrogen agonist/antagonist. An associated risk of endometrial cancer and hyperplasia has been linked to the estrogen agonist properties of tamoxifen. We evaluated endoxifen using a classic uterotrophic effects method. Rats were given endoxifen or tamoxifen orally for three days. Estradiol was the positive control. Endoxifen and tamoxifen plasma levels exceeded those previously observed clinically. Uterine weight was three-fold higher in the estradiol group than in the tamoxifen or endoxifen groups, which did not differ from vehicle controls. Tamoxifen and endoxifen caused a greater increase in luminal epithelial cell height than estradiol. Both tamoxifen and endoxifen produced an increase in the stromal BrdU labeling index (LI) that was ≤ estradiol and inversely related to dose, but did not affect luminal epithelial cell BrdU LI. As expected, estradiol increased luminal epithelial cell proliferation. These results indicate that endoxifen induces uterotrophic effects, but is less potent than estradiol in eliciting these effects. Given prior preclinical observations that endoxifen has superior antitumor activity than tamoxifen, the observations of similar uterine effects suggest that the endoxifen risk/benefit ratio may be superior to tamoxifen. PMID:24670817

  17. Adjuvant therapy of melanoma.

    PubMed

    Agarwala, S S; Kirkwood, J M

    1998-06-01

    Patients with AJCC Stage IIB and III melanoma have a poor 5-year survival rate which has been the driving force behind attempts to find an effective adjuvant therapy for this stage of disease that would effectively reduce relapse and improve survival. Immunotherapy with bacillus Calmette-Guerin (BCG), Corynebacterium parvum, and levamisole have not been successful in achieving this goal, nor have trials with chemotherapy in the adjuvant setting, including high-dose chemotherapy with autologous bone marrow transplantation. The recent Eastern Cooperative Oncology Group (ECOG) 1684 study showed significant improvement in relapse-free and overall survival with high doses of alpha interferon (IFNalpha) given for 1 year. Lower dosages of IFNalpha have to date been unsuccessful in impacting upon long-term survival. Recent data with vaccines have been encouraging, and the GM2-KLH vaccine is the focus of ongoing intergroup study comparing this treatment with IFNalpha in resected Stage IIB and III melanoma. The various regimens are reviewed in this article. PMID:9588723

  18. Linagliptin monotherapy compared with voglibose monotherapy in patients with type 2 diabetes undergoing hemodialysis: a 12-week randomized trial

    PubMed Central

    Mori, Katsuhito; Emoto, Masanori; Shoji, Tetsuo; Inaba, Masaaki

    2016-01-01

    Objective Focusing on efficacy and tolerability, we compared linagliptin monotherapy with voglibose monotherapy in patients with type 2 diabetes undergoing hemodialysis (HD). Research design and methods In this multicenter, randomized, open-label, parallel-group, active-controlled study, 78 patients were randomized (1:1) to receive a 12-week treatment with 5 mg linagliptin once daily or 0.2 mg voglibose three times a day. To assess whether linagliptin was superior to voglibose, the primary efficacy end point was the change in glycated hemoglobin (HbA1c) level between baseline and week 12. Secondary efficacy end points included changes between baseline and week 12 in glycated albumin (GA) and casual plasma glucose (PG) levels. Results At week 12, the adjusted mean HbA1c levels had decreased by −0.60% after treatment with linagliptin and by −0.20% after treatment with voglibose (treatment difference: −0.40%, 95% CI −0.74% to −0.06%, p=0.022). A significant reduction in casual PG level was also observed after treatment with linagliptin compared with treatment with voglibose. Relative to voglibose, linagliptin tended to elicit reductions in GA, although without statistical significance. No hypoglycemic symptoms or severe hypoglycemia occurred during the study. Conclusions In patients with type 2 diabetes undergoing HD, linagliptin monotherapy provided significantly better glycemic control without severe hypoglycemia than voglibose monotherapy. Linagliptin represents a promising agent for glycemic management in patients with type 2 diabetes undergoing HD. Trial registration number UMIN000007635; results. PMID:27547421

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

    PubMed Central

    Neonakis, Ioannis; Mantadakis, Elpis; Gitti, Zoe; Mitrouska, Ioanna; Manidakis, Louis George; Maraki, Sofia; Samonis, George

    2006-01-01

    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. PMID:16948834

  20. Tamoxifen ecotoxicity and resulting risks for aquatic ecosystems.

    PubMed

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

    2015-06-01

    Tamoxifen, a drug used to treat cancer, is regularly found in hydrosystems at concentrations of several hundred ng L(-1). To characterize its ecotoxicity, we implemented a battery of bioassays on organisms belonging to 3 different trophic levels: Pseudokirchneriella subcapitata, Chlorella vulgaris and Chlamydomonas reinhardtii, for primary producers, Daphnia magna (immobilization, grazing and reproduction) for primary consumers, and Danio rerio for secondary consumers (embryotoxicity test). In view of the results obtained and the ecotoxicity values of tamoxifen available in the literature, we established a PNEC (Predictive No Effect Concentration) equal to 81 ng L(-1) for continental water. This PNEC allowed us to calculate Risk Quotients (RQ) for 4 continental hydrosystems in 4 different countries in which measures of tamoxifen had already been performed on surface waters. In two of the situations studied, RQs were higher than 1, reaching a maximum of 2.6. These results show the need to deepen the characterization of ecotoxicological risks linked to the discharge of tamoxifen in surface waters. In addition, we propose applying this approach to other drug residues detected in the environment. PMID:25666175

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

    Cancer.gov

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

  2. Determination of Tamoxifen and its Major Metabolites in Exposed Fish

    EPA Science Inventory

    Tamoxifen (TAM), (Z)-1-(p-dimethylaminoethoxyphenyl)-1, 2-diphenyl-1-butene, is a nonsteroidal agent that has been used in breast cancer treatment for decades. Its major metabolites are 4-hydroxytamoxifen (4-OHT), N-desmethyltamoxifen (DMT), and endoxifen. While TAM and metabolit...

  3. Molecular signatures of vaccine adjuvants.

    PubMed

    Olafsdottir, Thorunn; Lindqvist, Madelene; Harandi, Ali M

    2015-09-29

    Mass vaccination has saved millions of human lives and improved the quality of life in both developing and developed countries. The emergence of new pathogens and inadequate protection conferred by some of the existing vaccines such as vaccines for tuberculosis, influenza and pertussis especially in certain age groups have resulted in a move from empirically developed vaccines toward more pathogen tailored and rationally engineered vaccines. A deeper understanding of the interaction of innate and adaptive immunity at molecular level enables the development of vaccines that selectively target certain type of immune responses without excessive reactogenicity. Adjuvants constitute an imperative element of modern vaccines. Although a variety of candidate adjuvants have been evaluated in the past few decades, only a limited number of vaccine adjuvants are currently available for human use. A better understanding of the mode of action of adjuvants is pivotal to harness the potential of existing and new adjuvants in shaping a desired immune response. Recent advancement in systems biology powered by the emerging cutting edge omics technology has led to the identification of molecular signatures rapidly induced after vaccination in the blood that correlate and predict a later protective immune response or vaccine safety. This can pave ways to prospectively determine the potency and safety of vaccines and adjuvants. This review is intended to highlight the importance of big data analysis in advancing our understanding of the mechanisms of actions of adjuvants to inform rational development of future human vaccines. PMID:25989447

  4. Extracorporeal shockwave lithotripsy monotherapy for large renal calculi.

    PubMed

    Gleeson, M J; Griffith, D P

    1989-10-01

    Extracorporeal shockwave lithotripsy (ESWL) monotherapy with a Dornier HM3 lithotripter was used to treat 199 large (greater than or equal to 3 cm) renal calculi. Calculi were classified as solitary (29), multiple (152) or staghorn (18) with stone-free rates of 55.2, 39.5 and 55.6% respectively. The stone-free rate was not statistically related to stone size, site or multiplicity. Complications occurred in 24 patients (12.8%) and were more common with solitary and staghorn calculi. ESWL is not recommended as primary treatment for most patients with large renal calculi.

  5. Mitogen-activated protein kinase phosphatase 1 is involved in tamoxifen resistance in MCF7 cells.

    PubMed

    Ma, Gang; Pan, Yixia; Zhou, Can; Sun, Ruifang; Bai, Jingjing; Liu, Peijun; Ren, Yu; He, Jianjun

    2015-11-01

    Tamoxifen resistance is a major clinical problem for ER-positive breast cancer, but the underlying mechanism is not completely elucidated. In the present study, we reported that mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1), a member of the family of MKPs, is involved in tamoxifen resistance. We found that MKP1 expression increased in tamoxifen resistant MCF7 cells. To explore the possible role of MKP1 in tamoxifen resistance, siRNA targeting MKP1 was transfected into tamoxifen resistant MCF7 cells. To our surprise, knockdown of MKP-1 promoted cell death induced by tamoxifen. On the other hand, the MKP1 overexpressed MCF7 cell clone was established and MKP1 overexpression effectively attenuated MCF7 cell death induced by tamoxifen. In addition, we revealed that MKP1 inhibited tamoxifen‑mediated JNK activation in tamoxifen resistant MCF7 and MCF7 cells, and by this mechanism MKP1 was able to inhibit tamoxifen-induced cell death. We also showed that combined appliaction of MKP1 inhibitor triptolide and tamoxifen can effectively increase tamoxifen sensitivity in tamoxifen resistant MCF7 cells. Collectively, our results indicated that MKP-1 can attenuate tamoxifen-induced cell death through inhibiting the JNK signal pathway, which represents a novel mechanism of tamoxifen resistance in MCF7 cells.

  6. Comparison of tamoxifen and letrozole response in mammary preneoplasia of ER and aromatase overexpressing mice defines an immune-associated gene signature linked to tamoxifen resistance.

    PubMed

    Dabydeen, Sarah A; Kang, Keunsoo; Díaz-Cruz, Edgar S; Alamri, Ahmad; Axelrod, Margaret L; Bouker, Kerrie B; Al-Kharboosh, Rawan; Clarke, Robert; Hennighausen, Lothar; Furth, Priscilla A

    2015-01-01

    Response to breast cancer chemoprevention can depend upon host genetic makeup and initiating events leading up to preneoplasia. Increased expression of aromatase and estrogen receptor (ER) is found in conjunction with breast cancer. To investigate response or resistance to endocrine therapy, mice with targeted overexpression of Esr1 or CYP19A1 to mammary epithelial cells were employed, representing two direct pathophysiological interventions in estrogen pathway signaling. Both Esr1 and CYP19A1 overexpressing mice responded to letrozole with reduced hyperplastic alveolar nodule prevalence and decreased mammary epithelial cell proliferation. CYP19A1 overexpressing mice were tamoxifen sensitive but Esr1 overexpressing mice were tamoxifen resistant. Increased ER expression occurred with tamoxifen resistance but no consistent changes in progesterone receptor, pSTAT3, pSTAT5, cyclin D1 or cyclin E levels in association with response or resistance were found. RNA-sequencing (RNA-seq) was employed to seek a transcriptome predictive of tamoxifen resistance using these models and a second tamoxifen-resistant model, BRCA1 deficient/Trp53 haploinsufficient mice. Sixty-eight genes associated with immune system processing were upregulated in tamoxifen-resistant Esr1- and Brca1-deficient mice, whereas genes related to aromatic compound metabolic process were upregulated in tamoxifen-sensitive CYP19A1 mice. Interferon regulatory factor 7 was identified as a key transcription factor regulating these 68 immune processing genes. Two loci encoding novel transcripts with high homology to human immunoglobulin lambda-like polypeptide 1 were uniquely upregulated in the tamoxifen-resistant models. Letrozole proved to be a successful alternative to tamoxifen. Further study of transcriptional changes associated with tamoxifen resistance including immune-related genes could expand our mechanistic understanding and lead to biomarkers predictive of escape or response to endocrine therapies

  7. Monotherapy or Polytherapy for First-Line Treatment of SE?

    PubMed

    Alvarez, Vincent; Rossetti, Andrea O

    2016-02-01

    Status epilepticus (SE) is one of the most frequent neurologic emergencies, and a rapid and effective treatment is warranted. Current guidelines recommend a stepwise approach using a sequence of different antiepileptic drugs with benzodiazepines (BZD) being the first treatment proposed. To provide the more effective treatment as soon as possible, some authors have suggested using a combined polytherapy as first-line treatment. Strong evidence supports the use of benzodiazepines, mostly lorazepam and midazolam as initial monotherapy treatment for SE. Insufficient data are available to support the use of nonsedating antiepileptic drugs as phenytoin, valproic acid, or levetiracetam without a previous benzodiazepine administration. Studies assessing the role of a combined initial therapy are rare, if not missing. Moreover, owing the wide range of SE etiologies, a "one fits all" initial polytherapy seems difficult to achieve. After reviewing the available evidence, guidelines, and current practices regarding monotherapy and polytherapy as first-line treatment in SE in adults, the authors propose a rational algorithm for early antiseizure treatment in SE. PMID:26840871

  8. ANTILYMPHOID ANTIBODY PRECONDITIONING AND TACROLIMUS MONOTHERAPY FOR PEDIATRIC KIDNEY TRANSPLANTATION

    PubMed Central

    Shapiro, Ron; Ellis, Demetrius; Tan, Henkie P.; Moritz, Michael L.; Basu, Amit; Vats, Abhay N.; Khan, Akhtar S.; Gray, Edward A.; Zeevi, Adrianna; McFeaters, Corde; James, Gerri; Grosso, Mary Jo; Marcos, Amadeo; Starzl, Thomas E.

    2010-01-01

    Objective Heavy post-transplant immunosuppression may contribute to long-term immunosuppression dependence by subverting tolerogenic mechanisms; thus, we sought to determine if this undesirable consequence could be mitigated by pretransplant lymphoid depletion and minimalistic post-transplant monotherapy. Study design Lymphoid depletion in 17 unselected pediatric recipients of live (n = 14) or deceased donor kidneys (n = 3) was accomplished with antithymocyte globulin (ATG) (n = 8) or alemtuzumab (n = 9). Tacrolimus was begun post-transplantation with subsequent lengthening of intervals between doses (spaced weaning). Maintenance immunosuppression, morbidity, graft function, and patient/graft survival were collated. Results Steroids were added temporarily to treat rejection in two patients (both ATG subgroup) or to treat hemolytic anemia in two others. After 16 to 31 months (mean 22), patient and graft survival was 100% and 94%, respectively. The only graft loss was in a nonweaned noncompliant recipient. In the other 16, serum creatinine was 0.85 ± 0.35 mg/dL and creatinine clearance was 90.8 ± 22.1 mL/1.73 m2. All 16 patients are on monotherapy (15 tacrolimus, one sirolimus), and 14 receive every other day or 3 times per week doses. There were no wound or other infections. Two patients developed insulin-dependent diabetes. Conclusion The strategy of lymphoid depletion and minimum post-transplant immunosuppression appears safe and effective for pediatric kidney recipients. PMID:16769394

  9. Innate immunity and adjuvants

    PubMed Central

    Akira, Shizuo

    2011-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  11. Tamoxifen and curcumin binding to serum albumin. Spectroscopic study

    NASA Astrophysics Data System (ADS)

    Maciążek-Jurczyk, M.; Maliszewska, M.; Pożycka, J.; Równicka-Zubik, J.; Góra, A.; Sułkowska, A.

    2013-07-01

    Tamoxifen (TMX) is widely used for the breast cancer treatment and is known as chemopreventive agent. Curcumin (CUR) is natural phenolic compound with broad spectrum of biological activity e.g. anti-inflammatory, antimicrobial, antiviral, antifungal and chemopreventive. Combination of tamoxifen and curcumin could be more effective with lower toxicity than each agent alone in use for the treatment or chemoprevention of breast cancer. Binding of drugs to serum albumin is an important factor, which determines toxicity and therapeutic dosage of the drugs. When two drugs are administered together the competition between them for the binding site on albumin can result in a decrease in bound fraction and an increase in the concentration of free biologically active fraction of drug.

  12. Luteal versus follicular phase surgical oophorectomy plus tamoxifen in premenopausal women with metastatic hormone receptor positive breast cancer

    PubMed Central

    Love, Richard R.; Hossain, Syed Mozammel; Hussain, Md. Margub; Mostafa, Mohammad Golam; Laudico, Adriano V.; Siguan, Stephen Sixto S.; Adebamowo, Clement; Sun, Jing-zhong; Fei, Fei; Shao, Zhi-Ming; Yunjiang, Liu; Akram Hussain, Syed Md.; Zhang, Baoning; Lin, Cheng; Panigaro, Sonar; Walta, Fardiana; Chuan, Jiang Hong; Mirasol-Lumague, Maria Rica; Yip, Cheng-Har; Navarro, Narciso S.; Huang, Chiun-sheng; Lu, Yen-shen; Ferdousy, Tahmina; Salim, Reza; Akhter, Chameli; Nahar, Shamsun; Uy, Gemma; Young, Gregory S.; Hade, Erinn M.; Jarjoura, David

    2016-01-01

    Purpose In premenopausal women with metastatic hormone receptor positive breast cancer, hormonal therapy is the first line therapy. GnRH + tamoxifen therapies have been found to be more effective. The pattern of recurrence risk over time after primary surgery suggests that peri-operative factors impact recurrence. Secondary analyses of an adjuvant trial suggested that the luteal phase timing of surgical oophorectomy in the menstrual cycle simultaneous with primary breast surgery favorably influenced long-term outcomes. Methods 249 premenopausal women with incurable or metastatic hormone receptor positive breast cancer entered a trial in which they were randomized to historical mid-luteal or mid-follicular phase surgical oophorectomy followed by oral tamoxifen treatment. Kaplan-Meier methods, the log-rank test, and multivariable Cox regression models were used to assess overall and progression free survival in the two randomized groups and by hormone confirmed menstrual cycle phase. Results Overall survival (OS) and progression-free survival were not demonstrated to be different in the two randomized groups. In a secondary analysis, OS appeared worse in luteal phase surgery patients with progesterone levels of <2ng/ml (anovulatory patients) (adjusted hazard ratio 1.46, 95% CI: 0.89–2.41, p=0.14) compared to patients in luteal phase with progesterone 2ng/ml or higher. Median overall survival was 2.0 years (95% CI: 1.7 – 2.3) and OS at 4 years was 26%. Conclusions The history-based timing of surgical oophorectomy in the menstrual cycle did not influence outcomes in this trial of metastatic patients. ClinicalTrials.gov number NCT 00293540 PMID:27107325

  13. Imaging tamoxifen retinopathy using spectral-domain optical coherence tomography

    PubMed Central

    Caramoy, Albert; Scholz, Paula; Fauser, Sascha; Kirchhof, Bernd

    2011-01-01

    A case of tamoxifen retinopathy examined with spectral-domain optical coherence tomography (SD-OCT) is presented. The typical refractile deposits are located between ganglion cell layer and inner plexiform layer in SD-OCT. A defect on the outer retinal layer with disruption of the photoreceptor layer with sharp edges is seen. The still attached posterior hyaloids gives evidence of other pathomechanism involved in the outer retinal defect than that of macular hole, as suggested in the literature.

  14. Virological efficacy of PI monotherapy for HIV-1 in clinical practice

    PubMed Central

    El Bouzidi, Kate; Collier, Dami; Nastouli, Eleni; Copas, Andrew J.; Miller, Robert F.; Gupta, Ravindra K.

    2016-01-01

    Background Clinical trials of PI monotherapy indicate that most participants maintain viral suppression and emergent protease resistance is rare. However, outcomes among patients receiving PI monotherapy for clinical reasons, such as toxicity or adherence issues, are less well studied. Methods An observational study of patients attending an HIV treatment centre in London, UK, who had received PI monotherapy between 2004 and 2013, was conducted using prospectively collected clinical data and genotypic resistance reports. Survival analysis techniques were used to examine the times to virological failure and treatment discontinuation. Results Ninety-five patients had PI monotherapy treatment for a median duration of 126 weeks. Virological failure occurred during 64% of episodes and 8% of patients developed emergent protease mutations. We estimate failure occurs in half of episodes within 2 years following initiation. Where PI monotherapy was continued following virological failure, 68% of patients achieved viral re-suppression. Despite a high incidence of virological failure, many patients continued PI monotherapy and 79% of episodes were ongoing at the end of the study. The type of PI used, the presence of baseline protease mutations and the plasma HIV RNA at initiation did not have a significant impact on treatment outcomes. Conclusions There was a higher incidence of virological failure and emerging resistance in our UK clinical setting than described in PI monotherapy clinical trials and other European observational studies. Despite this, many patients continued PI monotherapy and regained viral suppression, indicating this strategy remains a viable option in certain individuals following careful clinical evaluation. PMID:27402006

  15. Lymphocutaneous Sporotrichosis during Treatment with Anti-TNF-Alpha Monotherapy

    PubMed Central

    Ursini, Francesco; Calabria, Marilena; Bruno, Caterina; Tripolino, Cesare; Naty, Saverio; Grembiale, Rosa Daniela

    2015-01-01

    Sporotrichosis is an infectious disease caused by Sporothrix schenckii, a dimorphic fungus isolated for the first time in 1896 by Benjamin Schenck from a 36-year-old male patient presenting lesions on the right hand and arm. The infection generally occurs by traumatic inoculation of soil, plants, and organic matter contaminated with the fungus. Different clinical syndromes are described as a direct consequence of S. schenckii infection, including lymphocutaneous and disseminated forms, although extracutaneous presentations are reported most frequently in AIDS patients. Here we describe the case of a 57-year-old Caucasian male diagnosed in 2004 with ankylosing spondylitis under stable treatment with adalimumab monotherapy (40 mg every other week). During a routine follow-up visit in March 2013, he presented with multiple nodular lesions arranged in a linear fashion along the left hand and forearm. After diagnostic aspiration of the lesions, lymphocutaneous sporotrichosis was diagnosed and appropriate therapy started. PMID:25755904

  16. Mucosal adjuvants: Opportunities and challenges.

    PubMed

    Zeng, Lingbin

    2016-09-01

    Most pathogens access the body via mucosal surfaces. Mucosal vaccination is a highly effective and recommended method to prevent mucosally transmitted infections. Compared with immunization via intramuscular injection, mucosal immunization offers remarkable advantages, including non-invasiveness, low costs and reduced risk of transmission of blood-borne diseases, which make it more acceptable to human beings, especially to young children. However, only few mucosal vaccines are licensed for human, which is mainly due to the deficiency of safe and effective mucosal adjuvants. Adjuvants, as important components of most vaccines, are essential to enhance immunity and induce immune memory. The development of mucosal adjuvants, unfortunately, has been severely hampered by research strategies based on empiric trials and non-comprehensive methods for safety evaluation. Therefore, changing the research and development strategies of mucosal adjuvant field from empiricism based discovery to rational design based invention is highly demanded. The change of strategies mainly depends upon clarification of mechanism of mucosal adjuvant activity though a combination of life science, information science and materials science. PMID:27159278

  17. JC virus Reactivation During Prolonged Natalizumab Monotherapy for Multiple Sclerosis

    PubMed Central

    Chalkias, Spyridon; Dang, Xin; Bord, Evelyn; Stein, Marion C.; Kinkel, R. Philip; Sloane, Jacob A.; Donnelly, Maureen; Ionete, Carolina; Houtchens, Maria K.; Buckle, Guy J.; Batson, Stephanie; Koralnik, Igor J.

    2015-01-01

    Objective To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS). Methods We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy>18 months, 6 on interferon β-1a monotherapy>36 months and 5 untreated controls. We performed QPCR in cerebrospinal fluid (CSF), blood and urine for JCV DNA and we determined JCV-specific T cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides. Results JCV DNA was detected in the CSF of 2/27 (7.4%) natalizumab-treated MS patients who had no symptoms or MRI lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12/43 (27.9%) and in urine of 11/43 (25.6%) subjects without difference between natalizumab-treated patients and controls. JC viral load was higher in CD34+ cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot, and JCV-specific T cell responses, mediated by both CD4+ and CD8+ T-lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4+ T-cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34+ (p=0.05) and B cells (p=0.03). Interpretation Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34+ cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4+ T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment. PMID:24687904

  18. Lamotrigine monotherapy for newly diagnosed typical absence seizures in children☆

    PubMed Central

    Holmes, Gregory L.; Frank, L. Matthew; Sheth, Raj D.; Philbrook, Bryan; Wooten, John D.; Vuong, Alain; Kerls, Susan; Hammer, Anne E.; Messenheimer, John

    2008-01-01

    Summary Purpose To evaluate the efficacy, tolerability, and effects on behavior and psychosocial functioning of lamotrigine monotherapy in children with newly diagnosed typical absence seizures. Patients and methods Children meeting enrollment criteria (n = 54) received a confirmatory 24-h ambulatory electroencephalogram (EEG) and then entered a Escalation Phase of up to 20-weeks during which lamotrigine was titrated until seizures were controlled or maximum dose (10.2 mg/kg) was reached. Seizure freedom was assessed by diary review and clinic hyperventilation (clinic HV) and then confirmed by EEG with hyperventilation (HV/EEG). Patients who maintained seizure freedom for two consecutive weekly visits were entered into the Maintenance Phase (n = 30). Diary, clinic HV, and HV/EEG data were supplemented with 24-h ambulatory EEG at baseline and the ends of the Escalation and Maintenance Phases. Health outcome assessments were completed at screening and at the end of the Maintenance Phase. Results By the end of the Escalation Phase, seizure-free rates (responders) were 59% by seizure diary (n = 51), 56% by HV/EEG (n = 54) (primary endpoint), and 49% by 24-h ambulatory EEG (n = 49). During the Maintenance Phase, 89% (week 24) and 86% (week 32) remained seizure free by diary (n = 28), 78% by clinic HV (n = 27), and 81% by 24-h ambulatory EEG (n = 26). Seizure freedom was first observed beginning at the fifth week of the Escalation Phase. The most frequent adverse events were headache and cough. Health outcome scores were either improved or unchanged at the end of the Maintenance Phase. Conclusions Lamotrigine monotherapy results in complete seizure freedom in a substantial number of children with typical absence seizures. Lamotrigine was well tolerated in this study. PMID:18778916

  19. Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6.

    PubMed

    Sridar, Chitra; Kent, Ute M; Notley, Lisa M; Gillam, Elizabeth M J; Hollenberg, Paul F

    2002-06-01

    Tamoxifen is primarily used in the treatment of breast cancer. It has been approved as a chemopreventive agent for individuals at high risk for this disease. Tamoxifen is metabolized to a number of different products by cytochrome P450 enzymes. The effect of tamoxifen on the enzymatic activity of bacterially expressed human cytochrome CYP2B6 in a reconstituted system has been investigated. The 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity of purified CYP2B6 was inactivated by tamoxifen in a time- and concentration-dependent manner. Enzymatic activity was lost only in samples that were incubated with both tamoxifen and NADPH. The inactivation was characterized by a K(I) of 0.9 microM, a k(inact) of 0.02 min(-1), and a t(1/2) of 34 min. The loss in the 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity did not result in a similar percentage loss in the reduced carbon monoxide spectrum, suggesting that the heme moiety was not the major site of modification. The activity of CYP2B6 was not recovered after removal of free tamoxifen using spin column gel filtration. The loss in activity seemed to be due to a modification of the CYP2B6 and not reductase because adding fresh reductase back to the inactivated samples did not restore enzymatic activity. A reconstituted system containing purified CYP2B6, NADPH-reductase, and NADPH-generating system was found to catalyze tamoxifen metabolism to 4-OH-tamoxifen, 4'-OH-tamoxifen, and N-desmethyl-tamoxifen as analyzed by high-performance liquid chromatography analysis. Preliminary studies showed that tamoxifen had no effect on the activities of CYP1B1 and CYP3A4, whereas CYP2D6 and CYP2C9 exhibited a 25% loss in enzymatic activity. PMID:12023523

  20. Characterization of Tamoxifen as an Antifungal Agent Using the Yeast Schizosaccharomyces Pombe Model Organism.

    PubMed

    Zhang, Xibo; Fang, Yue; Jaiseng, Wurentuya; Hu, Lingling; Lu, Yabin; Ma, Yan; Furuyashiki, Tomoyuki

    2015-01-01

    Tamoxifen, a selective estrogen receptor modulator used for managing breast cancer, is known to have antifungal activity. However, its molecular mechanism remains unknown. Using the fission yeast Schizosaccharomyces pombe as a model organism, we have explored the mechanism involved in antifungal action of tamoxifen. Since tamoxifen was shown to inhibit the binding of calmodulin to calcineurin in fungi, we first examined involvement of these molecules and found that overexpression of a catalytic subunit of calcineurin and its constitutively active mutant as well as calmodulin increases tamoxifen sensitivity. Since terbinafine and azoles inhibit enzymes for ergosterol biosynthesis, Erg1 and Erg11, for their antifungal actions, we also examined involvement of these molecules. Overexpression of Erg1 and Erg11 reduced the sensitivity to terbinafine and azoles, respectively, but increased tamoxifen sensitivity, suggesting that ergosterol biosynthesis is differently related to the action of tamoxifen and those of terbinafine and azoles. To elucidate molecules involved in tamoxifen action, we performed a genome-wide screen for altered sensitivity to tamoxifen using a fission yeast gene deletion library, and identified various hypersensitive and resistant mutants to this drug. Notably, these mutants are rarely overlapped with those identified in similar genetic screens with currently used antifungals, suggesting a novel mode of antifungal action. Furthermore, tamoxifen augmented antifungal actions of terbinafine and azoles, suggesting synergetic actions between these drugs. Therefore, our findings suggest that calmodulin-calcineurin pathway and ergosterol biosynthesis are related to antifungal action of tamoxifen, and propose novel targets for antifungal development as well as combined therapy with tamoxifen for fungal diseases.

  1. Characterization of Tamoxifen as an Antifungal Agent Using the Yeast Schizosaccharomyces Pombe Model Organism.

    PubMed

    Zhang, Xibo; Fang, Yue; Jaiseng, Wurentuya; Hu, Lingling; Lu, Yabin; Ma, Yan; Furuyashiki, Tomoyuki

    2015-01-01

    Tamoxifen, a selective estrogen receptor modulator used for managing breast cancer, is known to have antifungal activity. However, its molecular mechanism remains unknown. Using the fission yeast Schizosaccharomyces pombe as a model organism, we have explored the mechanism involved in antifungal action of tamoxifen. Since tamoxifen was shown to inhibit the binding of calmodulin to calcineurin in fungi, we first examined involvement of these molecules and found that overexpression of a catalytic subunit of calcineurin and its constitutively active mutant as well as calmodulin increases tamoxifen sensitivity. Since terbinafine and azoles inhibit enzymes for ergosterol biosynthesis, Erg1 and Erg11, for their antifungal actions, we also examined involvement of these molecules. Overexpression of Erg1 and Erg11 reduced the sensitivity to terbinafine and azoles, respectively, but increased tamoxifen sensitivity, suggesting that ergosterol biosynthesis is differently related to the action of tamoxifen and those of terbinafine and azoles. To elucidate molecules involved in tamoxifen action, we performed a genome-wide screen for altered sensitivity to tamoxifen using a fission yeast gene deletion library, and identified various hypersensitive and resistant mutants to this drug. Notably, these mutants are rarely overlapped with those identified in similar genetic screens with currently used antifungals, suggesting a novel mode of antifungal action. Furthermore, tamoxifen augmented antifungal actions of terbinafine and azoles, suggesting synergetic actions between these drugs. Therefore, our findings suggest that calmodulin-calcineurin pathway and ergosterol biosynthesis are related to antifungal action of tamoxifen, and propose novel targets for antifungal development as well as combined therapy with tamoxifen for fungal diseases. PMID:26628015

  2. Adverse prognostic value of peritumoral vascular invasion: is it abrogated by adequate endocrine adjuvant therapy? Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy for early breast cancer

    PubMed Central

    Viale, G.; Giobbie-Hurder, A.; Gusterson, B. A.; Maiorano, E.; Mastropasqua, M. G.; Sonzogni, A.; Mallon, E.; Colleoni, M.; Castiglione-Gertsch, M.; Regan, M. M.; Brown, R. W.; Golouh, R.; Crivellari, D.; Karlsson, P.; Öhlschlegel, C.; Gelber, R. D.; Goldhirsch, A.; Coates, A. S.

    2010-01-01

    Background: Peritumoral vascular invasion (PVI) may assist in assigning optimal adjuvant systemic therapy for women with early breast cancer. Patients and methods: Patients participated in two International Breast Cancer Study Group randomized trials testing chemoendocrine adjuvant therapies in premenopausal (trial VIII) or postmenopausal (trial IX) node-negative breast cancer. PVI was assessed by institutional pathologists and/or central review on hematoxylin–eosin-stained slides in 99% of patients (analysis cohort 2754 patients, median follow-up >9 years). Results: PVI, present in 23% of the tumors, was associated with higher grade tumors and larger tumor size (trial IX only). Presence of PVI increased locoregional and distant recurrence and was significantly associated with poorer disease-free survival. The adverse prognostic impact of PVI in trial VIII was limited to premenopausal patients with endocrine-responsive tumors randomized to therapies not containing goserelin, and conversely the beneficial effect of goserelin was limited to patients whose tumors showed PVI. In trial IX, all patients received tamoxifen: the adverse prognostic impact of PVI was limited to patients with receptor-negative tumors regardless of chemotherapy. Conclusion: Adequate endocrine adjuvant therapy appears to abrogate the adverse impact of PVI in node-negative disease, while PVI may identify patients who will benefit particularly from adjuvant therapy. PMID:19633051

  3. Ethnic differences in initiation and timing of adjuvant endocrine therapy among older women with hormone receptor-positive breast cancer enrolled in Medicare Part D.

    PubMed

    Farias, Albert J; Du, Xianglin L

    2016-02-01

    The aim of this study was to determine whether there are racial/ethnic differences in initiation and timing of adjuvant endocrine therapy (AET) after Medicare Part D drug coverage. We conducted a retrospective cohort study using data from the Surveillance, Epidemiology, and End Results-Medicare-linked data to assess ethnic, socio-demographic, and tumor characteristic variations in the initiation of AET among patients ≥65 with hormone receptor-positive breast cancer in 2007-2009 enrolled in Medicare Part D through 2010. Logistic regression models were performed to assess the association between race/ethnicity and the initiation of tamoxifen, aromatase inhibitors (AIs), and overall AET (tamoxifen or AIs) within the first 12 months of diagnosis. Of the 12,198 women with hormone receptor-positive breast cancer, 74.8 % received AET within 12 months of diagnosis, of which 17.3 % received tamoxifen and 82.8 % received AIs. After controlling for all variables, only Asian women were found to have a greater odds of initiation of overall AET compared to non-Hispanic white women (odds ratio (OR): 1.28, 95 % CI: 1.03-1.58). Hispanic Mexicans and non-Hispanic black patients had a significantly lower odds of tamoxifen initiation (0.70, 0.54-0.91; 0.25, 0.10-0.62). For AI initiation, Hispanic Mexicans and Asians had a higher odds compared to non-Hispanic white women (2.06, 1.34-3.10; 1.33, 1.11-1.61). A suboptimal proportion of women (25.2 %) did not initiate AET within 12 months of diagnosis and therefore did not receive the full benefits of treatment to reduce the risk of breast cancer recurrence and mortality. Racial/ethnic differences in the initiation of tamoxifen and AIs have important implications that require further investigation.

  4. Endocrine therapy as adjuvant or neoadjuvant therapy for breast cancer: selecting the best agents, the timing and duration of treatment.

    PubMed

    Li, Jun-Jie; Shao, Zhi-Min

    2016-06-01

    Hormone receptor (HR) positive breast cancers represent the vast majority of breast cancers. Adjuvant and/or neoadjuvant endocrine therapy is highly effective and appropriate for nearly all women with HR positive tumors. Adjuvant tamoxifen (TAM) is a major endocrine treatment option, which has been found to be effective in both premenopausal and postmenopausal patients. Considerable evidence has been accrued of a benefit for ovarian ablation or suppression (OA/S) in premenopausal patients, for aromatase inhibitors (AIS) in postmenopausal patients, for the longer duration of adjuvant endocrine therapy and for the clinical utility of neoadjuvant endocrine therapy. Clinical practice guidelines should keep changing with developing evidence-based practice guidelines pertaining to breast cancer care. The present publication conducted a comprehensive systematic review of the literature addressing the use of endocrine therapy as adjuvant or neoadjuvant therapy for HR positive breast cancer, focusing on selecting the best agents for both premenopausal and postmenopausal patients, as well as the optimal duration of such treatment.

  5. The ultrastructure of tomatine adjuvant.

    PubMed

    Yang, Ya-Wun; Sheikh, Nadeem A; Morrow, W J W

    2002-12-01

    The tomatine adjuvant, consisting of tomatine, n-octyl-beta-D-glucopyranoside, phosphatidylethanolamine, cholesterol, and ovalbumin, has recently been shown to potentiate the immunogenicity of protein antigen and elicit cytotoxic T-lymphocyte responses in immunized animals. The physicochemical properties of tomatine adjuvant have not been characterized. The aim of this study was to examine the microstructure of this complex formulation, as directly related to its physicochemical properties. To elucidate the micromorphology of this system, the tomatine adjuvant was separated by isopycnic ultracentrifugation, followed by freeze fracturing and examination by transmission and scanning electron microscopy. The adjuvant mixture was shown to be composed of several micro- and nano-structures. The major fraction obtained from isopycnic separation was shown to consist of flaky needle-like microcrystals, approximately 80-160 nm in width and 2-4 microm in length. The tomatine crystals alone in 0.9% NaCl, on the other hand, were shown to be elongated hollow tubular crystals of hundreds of nanometers up to a few microns in length, along which n-octyl-beta-glucopyranoside was speculated to serve as a seeding microtemplate for gel crystallization of protein complexes. Indented marks within the gel phase were observed in the freeze fractured replicas of the adjuvant, suggesting that protein complexes may have been crystallized or precipitated within the gels. Several other forms of micro- and nano-structures were also observed, showing multiple-dispersion features with gel characteristics. The presence of gel crystalline and multiple-dispersed phases is postulated to contribute to the sustained immunopotentiation effect of tomatine adjuvant.

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

    SciTech Connect

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

    2013-11-15

    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

  7. THE INFLUENCE OF MAGNETIC FIELDS ON INHIBITION OF MCF-7 CELL GROWTH BY TAMOXIFEN

    EPA Science Inventory

    THE INFLUENCE OF MAGNETIC FIELDS ON INHIBITION OF MCF-7 CELL GROWTH BY TAMOXIFEN.
    Harland and Liburdy (1) reported that 1.2-uT, 60-Hz magnetic fields could significantly block the inhibitory action of pharmacological levels of tamoxifen (10-7 M) on the growth of MCF-7 human br...

  8. Light-Induced Toxic Effects of Tamoxifen: A Chemotherapeutic and Chemopreventive Agent

    PubMed Central

    Wang, Lei; Wang, Shuguang; Yin, Jun-Jie; Fu, Peter P.; Yu, Hongtao

    2009-01-01

    Tamoxifen is a powerful drug used to treat breast cancer patients, and more than 500,000 women in the U. S. are being treated with this drug. In our study, tamoxifen is found to be photomutagenic in Salmonella typhimurium TA102 at concentrations as low as 0.08 μM and reaches maximum photomutagenicity at 0.4 μM under a light dose equivalent to 20 min sunlight. These concentrations are comparable to the plasma tamoxifen concentration of 0.4 to 3 μM for patients undergoing tamoxifen therapy. The toxicity seems to be the result of DNA damage and/or lipid peroxidation caused by light irradiation of tamoxifen. The DNA damage caused by irradiation of ΦX174 DNA in the presence of tamoxifen appears to be formation of DNA-tamoxifen covalent adducts, not single strand/double strand cleavages, and there is no oxygen involvement. This is confirmed by EPR experiments that carbon-centerd radicals are formed by light irradiation of tamoxifen and there is no singlet oxygen formation. Although superoxide radical is formed, it is not involved in DNA damage. PMID:20046228

  9. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes.

    PubMed

    Madlensky, L; Natarajan, L; Tchu, S; Pu, M; Mortimer, J; Flatt, S W; Nikoloff, D M; Hillman, G; Fontecha, M R; Lawrence, H J; Parker, B A; Wu, A H B; Pierce, J P

    2011-05-01

    We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen and examined potential correlates of endoxifen concentration levels in serum including cytochrome P450 2D6 (CYP2D6) metabolizer phenotype and body mass index (BMI). Concentration levels of tamoxifen, endoxifen, 4-hydroxytamoxifen (4OH-tamoxifen), and N-desmethyltamoxifen (ND-tamoxifen) were measured from samples taken from 1,370 patients with estrogen receptor (ER)-positive breast cancer who were participating in the Women's Healthy Eating and Living (WHEL) Study. We tested these concentration levels for possible associations with breast cancer outcomes and found that breast cancer outcomes were not associated with the concentration levels of tamoxifen, 4-hydroxytamoxifen, and ND-tamoxifen. For endoxifen, a threshold was identified, with women in the upper four quintiles of endoxifen concentration appearing to have a 26% lower recurrence rate than women in the bottom quintile (hazard ratio (HR) = 0.74; 95% confidence interval (CI), (0.55-1.00)). The predictors of this higher-risk bottom quintile were poor/intermediate metabolizer genotype, higher BMI, and lower tamoxifen concentrations as compared with the mean for the cohort as a whole. This study suggests that there is a minimal concentration threshold above which endoxifen is effective against the recurrence of breast cancer and that ~80% of tamoxifen takers attain this threshold. PMID:21430657

  10. The Effect of Selective Estrogen Receptor Modulators (SERMs) on the Tamoxifen Resistant Breast Cancer Cells.

    PubMed

    Chang, Bo Yoon; Kim, Sae Am; Malla, Bindu; Kim, Sung Yeon

    2011-06-01

    Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to estrogen receptors (ER) and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the prototypical SERM, is extensively used for targeted therapy of ER positive breast cancers. Unfortunately, the use of tamoxifen is associated with acquired resistance and some undesirable side effects. This study investigated the availability of the conventional SERMs on the TAM-resistance breast cancer cells. SERMs showed more effectiveness in MCF-7 cells than tamoxifen resistant cells, except toremifene and ospemifene. Especially, toremifene was more efficacious in tamoxifen resistant cells than MCF-7. Ospemifene had similar cytotoxic activity on the two types of breast cancers. The other SERMs used in this experiment didn't inhibit efficiently the proliferation of tamoxifen resistant cells. These results support the possibility to usage of toremifene on tamoxifen resistant cancer. The effectiveness by toremifene on tamoxifen resistant cells might be different pathways from the apoptosis and the autophagy. Further study should be needed to elucidate the underlying mechanism of effect of toremifene on tamoxifen resistant cancer.

  11. Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells.

    PubMed

    Ignatov, Atanas; Ignatov, Tanja; Roessner, Albert; Costa, Serban Dan; Kalinski, Thomas

    2010-08-01

    Tamoxifen is the most frequently used anti-hormonal drug for treatment of women with hormone-dependent breast cancer. The aim of this study is to investigate the mechanism of tamoxifen resistance and the impact of the new estrogen G-protein coupled receptor (GPR30). MCF-7 cells were continuously exposed to tamoxifen for 6 months to induce resistance to the inhibitory effect of tamoxifen. These tamoxifen-resistant cells (TAM-R) exhibited enhanced sensitivity to 17-ss-estradiol and GPR30 agonist, G1, when compared to the parental cells. In TAM-R cells, tamoxifen was able to stimulate the cell growth and MAPK phosphorylation. These effects were abolished by EGFR inhibitor AG1478, GPR30 anti-sense oligonucleotide, and the selective c-Src inhibitor PP2. Only EGFR basal expression was slightly elevated in the TAM-R cells, whereas GPR30 expression and the basal phosphorylation of Akt and MAPK remained unchanged when compared to the parental cells. Interestingly, estrogen treatment significantly increased GPR30 translocation to the cell surface, which was stronger in TAM-R cells. Continuous treatment of MCF-7 cells with GPR30 agonist G1 mimics the long-term treatment with tamoxifen and increases drastically its agonistic activity. This data suggests the important role of GPR30/EGFR receptor signaling in the development of tamoxifen resistance. The inhibition of this pathway is a valid option to improve anti-hormone response in breast cancer.

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

    PubMed

    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.

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

    PubMed

    Cavalli, R; Bisazza, A; Bussano, R; Trotta, M; Civra, A; Lembo, D; Ranucci, E; Ferruti, P

    2011-01-01

    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. PMID:21785731

  14. Interaction of tamoxifen's impact on overall net mortality and quality of life.

    PubMed

    Ragaz, J

    1997-02-01

    Tamoxifen has well-documented activity in reducing breast cancer mortality. In addition, it has several secondary effects that may have an overall impact on long-term survival, and that are of particular importance in patients surviving the primary breast cancer. To fully understand the therapeutic role of tamoxifen, it is important to take into account survival differences related to all conditions known to be affected by tamoxifen. The purpose of this report is twofold. First, it provides information on mortality rates for conditions other than primary breast cancer in patients who survive the primary breast cancer, and the effect of tamoxifen on these mortality rates. Second, it outlines the principal side effects of tamoxifen that can affect quality of life and briefly summarizes their management.

  15. Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide.

    PubMed

    Corriden, Ross; Hollands, Andrew; Olson, Joshua; Derieux, Jaclyn; Lopez, Justine; Chang, John T; Gonzalez, David J; Nizet, Victor

    2015-01-01

    Tamoxifen is a selective oestrogen receptor modulator widely used for the treatment of breast cancer. In addition to its activity as an oestrogen receptor agonist/antagonist, tamoxifen also modulates sphingolipid biosynthesis, which has been shown to play an important role in the regulation of neutrophil activity. Here, we find that tamoxifen stimulation enhances several pro-inflammatory pathways in human neutrophils, including chemotaxis, phagocytosis and neutrophil extracellular trap (NET) formation. The enhancement of NET production occurs via a ceramide/PKCζ-mediated pathway, and treatment with synthetic ceramide is sufficient to promote NET formation. Pretreatment of human neutrophils with tamoxifen boosts neutrophil bactericidal capacity against a variety of pathogens in vitro and enhances clearance of the leading human pathogen methicillin-resistant Staphylococcus aureus in vivo. Our results suggest that tamoxifen, and the lipid signalling pathways it modulates, merit further exploration as targets for boosting host innate immune function. PMID:26458291

  16. Tamoxifen Augments the Innate Immune Function of Neutrophils Through Modulation of Intracellular Ceramide

    PubMed Central

    Corriden, Ross; Hollands, Andrew; Olson, Joshua; Derieux, Jaclyn; Lopez, Justine; Chang, John T.; Gonzalez, David J.; Nizet, Victor

    2015-01-01

    Tamoxifen is a selective estrogen receptor modulator widely used for the treatment of breast cancer. In addition to its activity as an estrogen receptor agonist/antagonist, tamoxifen also modulates sphingolipid biosynthesis, which has been shown to play an important role in the regulation of neutrophil activity. Here, we find that tamoxifen stimulation enhances several pro-inflammatory pathways in human neutrophils, including chemotaxis, phagocytosis and neutrophil extracellular trap (NET) formation. The enhancement of NET production occurs via a ceramide/PKCζ-mediated pathway, and treatment with synthetic ceramide is sufficient to promote NET formation. Pretreatment of human neutrophils with tamoxifen boosts neutrophil bactericidal capacity against a variety of pathogens in vitro and enhances clearance of the leading human pathogen methicillin-resistant Staphylococcus aureus in vivo. Our results suggest that tamoxifen, and the lipid signaling pathways it modulates, merit further exploration as targets for boosting host innate immune function. PMID:26458291

  17. QS-21: a potent vaccine adjuvant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    QS-21 is an potent adjuvant derived from the bark of a Chilean tree, Quillaja saponaria. One of the advantages of this adjuvant is that it promotes a balanced humoral and cell-mediaed immune response and can be widely applicable to a variety of vaccines. This adjuvant has used for some veterinary va...

  18. Longitudinal Change in Mammographic Density among ER-Positive Breast Cancer Patients Using Tamoxifen.

    PubMed

    Nyante, Sarah J; Sherman, Mark E; Pfeiffer, Ruth M; Berrington de Gonzalez, Amy; Brinton, Louise A; Bowles, Erin J Aiello; Hoover, Robert N; Glass, Andrew; Gierach, Gretchen L

    2016-01-01

    Tamoxifen-associated mammographic density (MD) reductions are linked to improved breast cancer survival. We evaluated MD at six time points to determine the timing of greatest reduction following tamoxifen initiation. We sampled 40 Kaiser Permanente Northwest estrogen receptor (ER)-positive breast cancer patients from a prior study of MD change, according to tamoxifen use duration and age at diagnosis: <4 years tamoxifen and ≤50 years (N = 6) or >50 years (N = 10) old; ≥4 years tamoxifen and ≤50 years (N = 13) or >50 years (N = 11) old. A single reader evaluated percent MD in the contralateral breast on baseline (pre-diagnosis) and five approximately yearly post-diagnostic (T1 to T5) mammograms. Mean MD change was calculated. Interactions with age (≤50 and >50 years), tamoxifen duration (<4 and ≥4 years), and baseline MD (tertiles) were tested in linear regression models. Overall, the largest MD decline occurred by T1 (mean 4.5%) with little additional decline by T5. Declines differed by tertile of baseline MD (Pinteraction < 0.01). In the highest tertile, the largest reduction occurred by T1 (mean 14.9%), with an additional reduction of 3.6% by T5. Changes were smaller in the middle and lowest baseline MD tertiles, with cumulative reductions of 3.0% and 0.4% from baseline to T5, respectively. There were no differences by age (Pinteraction = 0.36) or tamoxifen duration (Pinteraction = 0.42). Among ER-positive patients treated with tamoxifen and surviving ≥5 years, most of the MD reduction occurred within approximately 12 months of tamoxifen initiation, suggesting that MD measurement at a single time point following tamoxifen initiation can identify patients with substantial density declines. PMID:26545407

  19. Adjuvant therapy of malignant melanoma.

    PubMed

    Molife, R; Hancock, B W

    2002-10-01

    High risk surgically resected melanoma is associated with a less than 50% 5-year survival. Adjuvant therapy is an appropriate treatment modality in this setting, and is more likely to be effective as the tumour burden here is small. Clinical observations of spontaneous tumour regressions and a highly variable rate of disease progression suggest a role of the immune system in the natural history of melanoma. Biological agents have therefore been the subjects of numerous adjuvant studies. Early, randomised controlled trials (RCTs) of Bacillus Calmette-Guerin (BCG), levamisole, Corynebacterium parvum, chemotherapy, isolated limb perfusion (ILP), radiotherapy, transfer factor (TF), megestrol acetate and vitamin A yielded largely negative results. Current trials focus on vaccines and the interferons. To date the latter is the only therapy to have shown a significant benefit in the prospective randomised controlled phase III setting. This report represents a systematic review of studies in adjuvant therapy in melanoma. Data from ongoing studies is awaited before a role for adjuvant agents in high risk melanoma is confirmed. PMID:12399001

  20. Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC CTG MA.14 and NSABP B-29.

    PubMed

    Chapman, Judith-Anne W; Costantino, Joseph P; Dong, Bin; Margolese, Richard G; Pritchard, Kathleen I; Shepherd, Lois E; Gelmon, Karen A; Wolmark, Norman; Pollak, Michael N

    2015-09-01

    NCIC CTG MA.14 and NSABP B-29 trials examined the addition of Octreotide LAR (OCT) to 5 years of tamoxifen (TAM). Gallbladder toxicity led to B-29 discontinuation of OCT, and MA.14 OCT administration shortened to 2 years. Median follow-up was 9.8 years for 667 MA.14 patients and 6.8 years for 893 B-29 patients. The primary endpoint was disease-free survival (DFS), defined as time from randomization to time of breast cancer recurrence; second primary cancer other than squamous or basal cell skin carcinoma, cervical carcinoma in situ, or lobular breast carcinoma in situ; or death. The primary statistical test was a univariable pooled stratified log-rank test; multivariable assessment was with Cox regression. For MA.14, 97% of patients were ≥50 years; for B-29, 62%. MA.14 patients were 53% lymph node negative (LN-) while B-29 were 100% LN-; 33% of MA.14 patients received adjuvant chemotherapy, 2% concurrently, while B-29 had 53% concurrent chemotherapy. MA.14 patients were 90% hormone receptor positive; B-29, 100%. MA.14 patients experienced 5-year DFS of 80% with TAM, 76% with TAM + OCT; B-29 patients had 5-year DFS of 88% for both arms. Pooled univariable TAM + OCT to TAM hazard ratio (HR) was 0.99 (95% CI 0.81-1.20; p = 0.69): for MA.14, HR = 0.94 (0.73-1.20; p = 0.50); for B-29, HR = 1.09 (0.80-1.50; p = 0.59). Multivariable pooled HR = 0.98 (0.81-1.20; p = 0.84). Older patients (p < 0.001), with higher T stage (p < 0.001), and LN + (p < 0.001) had shorter DFS. Addition of OCT to TAM did not significantly improve DFS; gallbladder toxicity shortened the additional administration of OCT. This does not negate targeting the insulin-IGF-I receptor family with less toxic therapeutics.

  1. Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC CTG MA.14 and NSABP B-29

    PubMed Central

    Costantino, Joseph P.; Dong, Bin; Margolese, Richard G.; Pritchard, Kathleen I.; Shepherd, Lois E.; Gelmon, Karen A.; Wolmark, Norman; Pollak, Michael N.

    2015-01-01

    NCIC CTG MA.14 and NSABP B-29 trials examined the addition of Octreotide LAR (OCT) to 5 years of tamoxifen (TAM). Gallbladder toxicity led to B-29 discontinuation of OCT, and MA.14 OCT administration shortened to 2 years. Median follow-up was 9.8 years for 667 MA.14 patients and 6.8 years for 893 B-29 patients. The primary endpoint was disease-free survival (DFS), defined as time from randomization to time of breast cancer recurrence; second primary cancer other than squamous or basal cell skin carcinoma, cervical carcinoma in situ, or lobular breast carcinoma in situ; or death. The primary statistical test was a univariable pooled stratified log-rank test; multivariable assessment was with Cox regression. For MA.14, 97 % of patients were ≥50 years; for B-29, 62 %. MA.14 patients were 53 % lymph node negative (LN–) while B-29 were 100 % LN–; 33 % of MA.14 patients received adjuvant chemotherapy, 2 % concurrently, while B-29 had 53 % concurrent chemotherapy. MA.14 patients were 90% hormone receptor positive; B-29, 100 %. MA.14 patients experienced 5-year DFS of 80 % with TAM, 76 % with TAM + OCT; B-29 patients had 5-year DFS of 88 % for both arms. Pooled univariable TAM + OCT to TAM hazard ratio (HR) was 0.99 (95% CI 0.81–1.20; p = 0.69): for MA.14, HR = 0.94 (0.73–1.20; p = 0.50); for B-29, HR = 1.09 (0.80–1.50; p = 0.59). Multivariable pooled HR = 0.98 (0.81–1.20; p = 0.84). Older patients (p < 0.001), with higher T stage (p < 0.001), and LN + (p < 0.001) had shorter DFS. Addition of OCT to TAM did not significantly improve DFS; gallbladder toxicity shortened the additional administration of OCT. This does not negate targeting the insulin–IGF-I receptor family with less toxic therapeutics. PMID:26276354

  2. Density Functional Study of the structural properties in Tamoxifen

    NASA Astrophysics Data System (ADS)

    de Coss-Martinez, Romeo; Tapia, Jorge A.; Quijano-Quiñones, Ramiro F.; Canto, Gabriel I.

    2013-03-01

    Using the density functional theory, we have studied the structural properties of Tamoxifen. The calculations were performed with two methodological approaches, which were implemented in SIESTA and Spartan codes. For SIESTA, we considerate a linear combination of atomic orbitals method, using pseudopotentials and the van der Waals approximation for the exchange-correlation potential. Here we analyzed and compared the atomic structure between our results and other theoretical study. We found differences in the bond lengths between the results, that could be attributed to code approaches in each one. This work was supported under Grant FOMIX 2011-09 N: 170297 of Ph.D. A. Tapia.

  3. [Adjuvants in modern medicine and veterinary].

    PubMed

    Kozlov, V G; Ozherelkov, S V; Sanin, A V; Kozhevnikova, T N

    2014-01-01

    The review is dedicated to immunologic adjuvants--various natural and synthetics substances that are added to vaccines for stimulation of specific immune response, but they do not induce specific response themselves. Critically important is the selection of the correct adjuvants, for which mechanisms of effect on immune system are studied the most. The majority of these mechanisms as well as physical-chemical and biological features of modern adjuvants are analyzed in the review. The problem of safety of adjuvants, types of immune response induced by adjuvants of various nature, excipients that are being verified or already in use in modern medicine and veterinary are also examined.

  4. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial.

    PubMed

    Praga, M; Barrio, V; Juárez, G Fernández; Luño, J

    2007-05-01

    Membranous nephropathy is a common cause of nephrotic syndrome in adults. Although some patients with membranous nephropathy achieve a spontaneous remission, renal function continues to deteriorate in others. We conducted a prospective randomized trial evaluating monotherapy with tacrolimus to achieve complete or partial remission in patients with biopsy-proven membranous nephropathy. Twenty-five patients received tacrolimus (0.05 mg/kg/day) over 12 months with a 6-month taper, whereas 23 patients were in the control group. The probability of remission in the treatment group was 58, 82, and 94% after 6, 12, and 18 months but only 10, 24, and 35%, respectively in the control group. The decrease in proteinuria was significantly greater in the treatment group. Notably, six patients in the control group and only one in the treatment group reached the secondary end point of a 50% increase in their serum creatinine. No patient in the tacrolimus group showed a relapse during the taper period. Nephrotic syndrome reappeared in almost half of the patients who were in remission by the 18th month after tacrolimus withdrawal. We conclude that tacrolimus is a very useful therapeutic option for patients with membranous nephropathy and preserved renal function. The majority of patients experienced remission with a significant reduction in the risk for deteriorating renal function.

  5. Vaccine adjuvants as potential cancer immunotherapeutics.

    PubMed

    Temizoz, Burcu; Kuroda, Etsushi; Ishii, Ken J

    2016-07-01

    Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304

  6. Vaccine adjuvants as potential cancer immunotherapeutics

    PubMed Central

    Temizoz, Burcu; Kuroda, Etsushi

    2016-01-01

    Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund’s adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy. PMID:27006304

  7. Advances and challenges in mucosal adjuvant technology.

    PubMed

    Newsted, Daniel; Fallahi, Firouzeh; Golshani, Ashkan; Azizi, Ali

    2015-05-15

    Adjuvants play attractive roles in enhancement of immune response during vaccination; however, due to several challenges, only a limited number of adjuvants are licensed by health authorities. The lack of an effective mucosal adjuvant is even more significant as none of the licensed adjuvants revealed a strong enhancement in immune system after mucosal administration. Over the past two decades, several mucosal adjuvants have been developed to deliver antigens to the target cells in the mucosal immune system and increase specific immune responses. However, the safety and efficacy of these adjuvants for testing in human trials is still an important issue, requiring further study. In this article, we briefly review the challenges associated with most common mucosal adjuvants and discuss potential strategies for targeting the mucosal immune system.

  8. Improving vaccine delivery using novel adjuvant systems.

    PubMed

    Pichichero, Michael E

    2008-01-01

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

  9. mTOR inhibitors counteract tamoxifen-induced activation of breast cancer stem cells.

    PubMed

    Karthik, Govindasamy-Muralidharan; Ma, Ran; Lövrot, John; Kis, Lorand Levente; Lindh, Claes; Blomquist, Lennart; Fredriksson, Irma; Bergh, Jonas; Hartman, Johan

    2015-10-10

    Breast cancer cells with stem cell characteristics (CSC) are a distinct cell population with phenotypic similarities to mammary stem cells. CSCs are important drivers of tumorigenesis and the metastatic process. Tamoxifen is the most widely used hormonal therapy for estrogen receptor (ER) positive cancers. In our study, tamoxifen was effective in reducing proliferation of ER + adherent cancer cells, but not their CSC population. We isolated, expanded and incubated CSC from seven breast cancers with or without tamoxifen. By genome-wide transcriptional analysis we identified tamoxifen-induced transcriptional pathways associated with ribosomal biogenesis and mRNA translation, both regulated by the mTOR-pathway. We observed induction of the key mTOR downstream targets S6K1, S6RP and 4E-BP1 in-patient derived CSCs by tamoxifen on protein level. Using the mTOR inhibitors rapamycin, everolimus and PF-04691502 (a dual PI3K/mTOR inhibitor) and in combination with tamoxifen, significant reduction in mammosphere formation was observed. Hence, we suggest that the CSC population play a significant role during endocrine resistance through activity of the mTOR pathway. In addition, tamoxifen further stimulates the mTOR-pathway but can be antagonized using mTOR-inhibitors. PMID:26208432

  10. Minireview: The Link Between ERα Corepressors and Histone Deacetylases in Tamoxifen Resistance in Breast Cancer.

    PubMed

    Légaré, Stéphanie; Basik, Mark

    2016-09-01

    Approximately 70% of breast cancers express the estrogen receptor (ER)α and are treated with the ERα antagonist, tamoxifen. However, resistance to tamoxifen frequently develops in advanced breast cancer, in part due to a down-regulation of ERα corepressors. Nuclear receptor corepressors function by attenuating hormone responses and have been shown to potentiate tamoxifen action in various biological systems. Recent genomic data on breast cancers has revealed that genetic and/or genomic events target ERα corepressors in the majority of breast tumors, suggesting that the loss of nuclear receptor corepressor activity may represent an important mechanism that contributes to intrinsic and acquired tamoxifen resistance. Here, the biological functions of ERα corepressors are critically reviewed to elucidate their role in modifying endocrine sensitivity in breast cancer. We highlight a mechanism of gene repression common to corepressors previously shown to enhance the antitumorigenic effects of tamoxifen, which involves the recruitment of histone deacetylases (HDACs) to DNA. As an indicator of epigenetic disequilibrium, the loss of ERα corepressors may predispose cancer cells to the cytotoxic effects of HDAC inhibitors, a class of drug that has been shown to effectively reverse tamoxifen resistance in numerous studies. HDAC inhibition thus appears as a promising therapeutic approach that deserves to be further explored as an avenue to restore drug sensitivity in corepressor-deficient and tamoxifen-resistant breast cancers. PMID:27581354

  11. Omega-3 free fatty acids inhibit tamoxifen-induced cell apoptosis.

    PubMed

    Wu, Shufan; Guo, Yang; Wu, Yikuan; Zhu, Shenglong; He, Zhao; Chen, Yong Q

    2015-04-01

    Fish oil, which contains omega-3 fatty acids mainly in the form of triglycerides, has benefits for reducing breast cancer risk, similar to tamoxifen action. However, it remains to be elucidated whether the combination of omega-3 free fatty acid (ω-3FFA) with tamoxifen leads to improved treatment in breast cancer. In this study, we observed that ω-3FFA induces MCF-7 cell apoptosis to suppress cell growth. The treatment of breast cancer cells with ω-3FFA attenuated tamoxifen-induced cell apoptosis. ω-3FFA and tamoxifen significantly increased Erk1/2 and Akt phosphorylation levels in a dose and time dependent manner. Compared to ω-3FFA alone, the combination of tamoxifen with ω-3FFA significantly increased Erk1/2 and Akt phosphorylation levels. Because Erk1/2 and Akt activation has been linked to tamoxifen-related anti-estrogen resistance in breast cancer patients, these results indicate that ω-3FFA may interfere with the effects of tamoxifen in the prevention of breast cancer risk.

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

    SciTech Connect

    Wang Ying; He Qingyu; Chen Hongming; Chiu Jenfu . E-mail: jfchiu@hkucc.hku.hk

    2007-01-15

    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 {beta} (TGF{beta}) 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 TGF{beta} treatment, or co-treatment with TGF{beta} inhibitor SB 431542, proteomic results showed that a number of proteins were involved in TGF{beta} signaling pathway. These results provide valuable insights into the mechanisms of RA and tamoxifen-induced TGF{beta} signaling pathway in breast cancer cells.

  13. Cytochrome P450 2D6 Activity Predicts Discontinuation of Tamoxifen Therapy in Breast Cancer Patients

    PubMed Central

    Rae, James M.; Sikora, Matthew J.; Henry, N. Lynn; Li, Lang; Kim, Seongho; Oesterreich, Steffi; Skaar, Todd; Nguyen, Anne T.; Desta, Zeruesenay; Storniolo, Anna Maria; Flockhart, David A.; Hayes, Daniel F.; Stearns, Vered

    2009-01-01

    The selective estrogen receptor modulator tamoxifen is routinely used for treatment and prevention of estrogen receptor positive breast cancer. Studies of tamoxifen adherence suggest that over half of patients discontinue treatment before the recommended 5 years. We hypothesized that polymorphisms in CYP2D6, the enzyme responsible for tamoxifen activation, predict for tamoxifen discontinuation. Tamoxifen-treated women (n = 297) were genotyped for CYP2D6 variants and assigned a “score” based on predicted allele activities from 0 (no activity) to 2 (high activity). Correlation between CYP2D6 score and discontinuation rates at 4 months were tested. We observed a strong non-linear correlation between higher CYP2D6 score and increased rates of discontinuation (r2 = 0.935, p = 0.018). These data suggest that presence of active CYP2D6 alleles may predict for higher likelihood of tamoxifen discontinuation. Therefore, patients who may be most likely to benefit from tamoxifen may paradoxically be most likely to discontinue treatment prematurely. PMID:19421167

  14. In vitro percutaneous absorption enhancement of a lipophilic drug tamoxifen by terpenes.

    PubMed

    Gao, S; Singh, J

    1998-02-12

    Tamoxifen is a highly lipophilic drug that is widely used in breast malignancies and also as a prophylactic therapy in women at high risk for the development of this disease. Recently, the terpenes have been reported to show an enhancement effect on percutaneous drug absorption. The effect of terpenes (e.g. carvone, 1,8-cineole, menthol, and thymol) was studied on the in vitro percutaneous absorption of tamoxifen through porcine epidermis. The above terpenes (5% w/v) in combination with 50% ethanol significantly (P < 0.01) increased the permeability coefficient of tamoxifen in comparison to the control (50% ethanol). The solubility of tamoxifen was determined in the control and enhancer solutions to correct the permeability enhancement by way of fractional solubility adjustment. Binding of tamoxifen to powdered stratum corneum from control and enhancer solutions was also determined. Binding studies reveal that the enhancement in the permeability coefficient of tamoxifen by menthol and thymol is due at least in part, to improvement in the partitioning of the drug to the stratum corneum. In conclusion, terpenes in combination with ethanol can be used to enhance the percutaneous absorption of the highly lipophilic drug tamoxifen. PMID:9685917

  15. Estrogen Receptor Genotypes, Menopausal Status, and the Lipid Effects of Tamoxifen

    PubMed Central

    Ntukidem, NI; Nguyen, AT; Stearns, V; Rehman, M; Schott, A; Skaar, T; Jin, Y; Blanche, P; Li, L; Lemler, S; Hayden, J; Krauss, RM; Desta, Z; Flockhart, DA

    2009-01-01

    Tamoxifen induces important changes in serum lipid profiles in some women; however, little information is available to predict which women will experience improved lipid profiles during tamoxifen therapy. As part of a multicenter prospective observational trial in 176 breast cancer patients, we tested the hypothesis that tamoxifen-induced lipid changes were associated with genetic variants in candidate target genes (CYP2D6, ESR1, and ESR2). Tamoxifen lowered low-density lipoprotein cholesterol (P<0.0001) by 23.5mg/dl (13.5–33.5mg/dl) and increased triglycerides (P=0.006). In postmenopausal women, the ESR1-XbaI and ESR2-02 genotypes were associated with tamoxifen-induced changes in total cholesterol (P=0.03; GG vs GA/AA) and triglycerides (P=0.01; gene–dose effect), respectively. In premenopausal women, the ESR1-XbaI genotypes were associated with tamoxifen-induced changes in triglycerides (P=0.002; gene–dose effect) and high-density lipoprotein (P=0.004; gene–dose effect). Our results suggest that estrogen receptor genotyping may be useful in predicting which women would benefit more from tamoxifen. PMID:17713466

  16. Neoadjuvant tamoxifen synchronizes ERα binding and gene expression profiles related to outcome and proliferation

    PubMed Central

    Severson, Tesa M.; Nevedomskaya, Ekaterina; Peeters, Justine; Kuilman, Thomas; Krijgsman, Oscar; van Rossum, Annelot; Droog, Marjolein; Kim, Yongsoo; Koornstra, Rutger; Beumer, Inès; Glas, Annuska M.; Peeper, Daniel; Wesseling, Jelle; Simon, Iris M.; Wessels, Lodewyk; Linn, Sabine C.; Zwart, Wilbert

    2016-01-01

    Estrogen receptor alpha (ERα)-positive breast cancers are frequently treated with tamoxifen, but resistance is common. It remains elusive how tamoxifen resistance occurs and predictive biomarkers for treatment outcome are needed. Because most biomarker discovery studies are performed using pre-treatment surgical resections, the effects of tamoxifen therapy directly on the tumor cell in vivo remain unexamined. In this study, we assessed DNA copy number, gene expression profiles and ERα/chromatin binding landscapes on breast tumor specimens, both before and after neoadjuvant tamoxifen treatment. We observed neoadjuvant tamoxifen treatment synchronized ERα/chromatin interactions and downstream gene expression, indicating that hormonal therapy reduces inter-tumor molecular variability. ERα-synchronized sites are associated with dynamic FOXA1 action at these sites, which is under control of growth factor signaling. Genes associated with tamoxifen-synchronized sites are capable of differentiating patients for tamoxifen benefit. Due to the direct effects of therapeutics on ERα behavior and transcriptional output, our study highlights the added value of biomarker discovery studies after neoadjuvant drug exposure. PMID:27129152

  17. Tamoxifen inhibits nitrobenzylthioinosine-sensitive equilibrative uridine transport in human MCF-7 breast cancer cells.

    PubMed Central

    Cai, J; Lee, C W

    1996-01-01

    Tamoxifen inhibits the binding of [3H]nitrobenzylthioinosine ([3H]NBMPR) to human MCF-7 breast cancer cells with an IC50 of 8 microM. Tamoxifen at 30 microM changed the apparent Kd for [3H]NBMPR binding from 0.63 +/- 0.12 to 4.75 +/- 0.58 nM, with little effect on the Bmax (311000 +/- 76000 and 263000 +/- 46000 sites per cell for untreated and tamoxifen-treated cells respectively). Corresponding to this decrease in binding of [3H]NBMPR in the presence of tamoxifen was an inhibition of NBMPR-sensitive equilibrative transport of 50 microM [3H]uridine (IC50 7-10 microM). In the presence of 15 microM tamoxifen, the apparent K(m) for [3H]uridine transport was increased from 390 +/- 30 to 1500 +/- 250 microM, with no change in Vmax (12.0 +/- 0.1 and 11.3 +/- 4.3 microM/s for untreated and tamoxifen-treated cells respectively). The inhibitory effect of tamoxifen on NBMPR-sensitive equilibrative uridine transport was specific, as similar results were also observed in HL-60 leukaemia and EL4 lymphoma cells. Furthermore a similar concentration of tamoxifen had no effect on the NBMPR-insensitive equilibrative transport of uridine in MCF-7, HL-60 and Morris 7777 hepatoma cells, and on the Na(+)-dependent transport of uridine in murine splenocytes. In this paper we demonstrate that tamoxifen by itself might have some antiproliferative effects through inhibition of DNA synthesis by blocking the nucleoside salvage pathway. PMID:9003390

  18. Bioanalytical methods for determination of tamoxifen and its phase I metabolites: a review.

    PubMed

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

    2010-12-17

    The selective estrogen receptor modulator tamoxifen is used in the treatment of early and advanced breast cancer and in selected cases for breast cancer prevention in high-risk subjects. The cytochrome P450 enzyme system and flavin-containing monooxygenase are responsible for the extensive metabolism of tamoxifen into several phase I metabolites that vary in toxicity and potencies towards estrogen receptor (ER) alpha and ER beta. An extensive overview of publications on the determination of tamoxifen and its phase I metabolites in biological samples is presented. In these publications techniques were used such as capillary electrophoresis, liquid, gas and thin layer chromatography coupled with various detection techniques (mass spectrometry, ultraviolet or fluorescence detection, liquid scintillation counting and nuclear magnetic resonance spectroscopy). A trend is seen towards the use of liquid chromatography coupled to mass spectrometry (LC-MS). State-of-the-art LC-MS equipment allowed for identification of unknown metabolites and quantification of known metabolites reaching lower limit of quantification levels in the sub pg mL(-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. PMID:21094378

  19. ObRb downregulation increases breast cancer cell sensitivity to tamoxifen.

    PubMed

    Qian, Yingying; Shi, Dongmin; Qiu, Jinrong; Zhu, Fang; Qian, Jing; He, Shaohua; Shu, Yongqian; Yin, Yongmei; Chen, Xiaofeng

    2015-09-01

    Leptin is a potent adipokine that plays an important role in the progression of breast cancer and interferes with the action of tamoxifen. We investigated the molecular mechanism underlying the effect of leptin on tamoxifen resistance in breast cancer cells that express leptin receptor (ObRb), and evaluated the impact of ObRb suppression on tamoxifen treatment in MCF-7 and tamoxifen-resistant (TAM-R) cells. Leptin-induced signaling pathway activation was examined by qRT-PCR and Western blotting. Chromatin immunoprecipitation assays were performed to further examine the binding of estrogen receptor (ER) α on the promoter of cyclin D1 (CCND1) gene. The effects of combined ObRb knockdown and tamoxifen treatment were evaluated in MCF-7 and TAM-R cells. We found that the enhanced proliferation effects induced by leptin were related to extracellular-signal-regulated kinase (ERK) 1/2 and signal transducers and activators of transcription (STAT) 3 signaling pathway activation and CCND1 upregulation. Leptin enhanced CCND1 gene transcription by inducing the binding of ERα to the promoter of CCND1 gene. ObRb knockdown significantly enhanced the inhibitory effects of tamoxifen on TAM-R cell proliferation and survival. This study suggested that long-term endocrine therapy facilitates leptin and ObRb overexpression in breast cancer cells, which attenuates the inhibitory effect of tamoxifen by activating both the ERK1/2 and STAT3 signaling pathways and upregulating CCND1 gene expression. Combination therapy involving ObRb knockdown and tamoxifen treatment may be an alternative therapeutic option for tamoxifen-resistant breast cancer.

  20. Adjuvant therapy for endometrial cancer

    PubMed Central

    DeLeon, Maria C.; Ammakkanavar, Natraj R.

    2014-01-01

    Endometrial cancer is a common gynecologic malignancy typically diagnosed at early stage and cured with surgery alone. Adjuvant therapy is tailored according to the risk of recurrence, estimated based on the International Federation of Gynecology and Obstetrics (FIGO) stage and other histological factors. The objective of this manuscript is to review the evidence guiding adjuvant therapy for early stage and locally advanced uterine cancer. For patients with early stage disease, minimizing toxicity, while preserving outstanding cure rates remains the major goal. For patients with locally advanced endometrial cancer optimal combined regimens are being defined. Risk stratification based on molecular traits is under development and may aid refine the current risk prediction model and permit personalized approaches for women with endometrial cancer. PMID:24761218

  1. Biosafe Nanoscale Pharmaceutical Adjuvant Materials

    PubMed Central

    Jin, Shubin; Li, Shengliang; Wang, Chongxi; Liu, Juan; Yang, Xiaolong; Wang, Paul C.; Zhang, Xin; Liang, Xing-Jie

    2014-01-01

    Thanks to developments in the field of nanotechnology over the past decades, more and more biosafe nanoscale materials have become available for use as pharmaceutical adjuvants in medical research. Nanomaterials possess unique properties which could be employed to develop drug carriers with longer circulation time, higher loading capacity, better stability in physiological conditions, controlled drug release, and targeted drug delivery. In this review article, we will review recent progress in the application of representative organic, inorganic and hybrid biosafe nanoscale materials in pharmaceutical research, especially focusing on nanomaterial-based novel drug delivery systems. In addition, we briefly discuss the advantages and notable functions that make these nanomaterials suitable for the design of new medicines; the biosafety of each material discussed in this article is also highlighted to provide a comprehensive understanding of their adjuvant attributes. PMID:25429253

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

    PubMed

    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.

  3. Study of experimental endometriosis using fluorescence of eosin-tamoxifen association

    NASA Astrophysics Data System (ADS)

    Brogniez, A.; Mordon, Serge R.; Devoisselle, Jean-Marie; Querleu, Denis; Brunetaud, Jean Marc

    1993-08-01

    The main problem of endometriosis is the detection of microscopic and atypical lesions. The successful destruction of these endometriotic sites depends on their detection. This study aimed to develop a spectrofluorometric method to increase the sensitivity of detection of endometriosis. A surgical-induced endometriosis was performed in ten rabbits. Five weeks later, the fluorescence of these endometriotic lesions was studied after injection of tamoxifen and local application of eosin. This fluorescence was compared with that of healthy broad ligament and that obtained without tamoxifen and without eosin. A spectral analysis showed a specific fluorescence of eosin-tamoxifen association, more intense than autofluorescence and selectively observed within endometriosis.

  4. Adjuvant progestagens for endometrial cancer

    PubMed Central

    Martin-Hirsch, Pierre PL; Bryant, Andrew; Keep, Sarah L; Kitchener, Henry C; Lilford, Richard

    2014-01-01

    Background Endometrial cancer is the most common genital tract carcinoma among women in developed countries, with most women presenting with stage 1 disease. Adjuvant progestagen therapy has been advocated following primary surgery to reduce the risk of recurrence of disease. Objectives To evaluate the effectiveness and safety of adjuvant progestagen therapy for the treatment of endometrial cancer. Search methods We searched the Cochrane Gynaecological Cancer Group Trials Specilaised Register, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2009. MEDLINE and EMBASE up to April 2009. Selection criteria Randomised controlled trials (RCTs) of progestagen therapy in women who have had surgery for endometrial cancer. Data collection and analysis Two review authors independently abstracted data and assessed risk of bias. Risk ratios (RRs) comparing survival in women who did and did not receive progestagen were pooled in random effects meta-analyses.. Main results Seven trials assessing 4556 women were identified. Three trials included women with stage one disease only, whereas four included women with more advanced disease. Meta-analysis of four trials showed that there was no significant difference in the risk of death at five years between adjuvant progestagen therapy and no further treatment (RR = 1.00, 95% CI 0.85 to 1.18). This conclusion is also robust to single trial analyses at 4 and 7 years and in one trial across all points in time using a hazard ratio (HR). There was also no significant difference between progestagen therapy and control in terms of the risk of death from endometrial cancer, cardiovascular disease and intercurrent disease. Relapse of disease appeared to be reduced by progestagen therapy in one trial (HR = 0.71, 95% CI 0.52 to 0.97 and 5 year RR = 0.74, 95% CI 0.58 to 0.96), but there was no evidence of a difference in disease recurrence in another trial at 7 years (RR = 1.34, 95% CI 0.79 to 2.27). Authors’ conclusions There

  5. Adjuvant therapy use among Appalachian breast cancer survivors.

    PubMed

    Tan, Xi; Marshall, Vincent D; Anderson, Roger T; Donohoe, Joseph; Camacho, Fabian; Balkrishnan, Rajesh

    2015-07-01

    There is a paucity of literature systemically examining the effects of access to cancer care resources on adjuvant endocrine therapy (AET) use behaviors, especially in underserved regions such as the Appalachian region in the United States, where gaps in healthcare access are well documented. The objectives of this study were to explore AET adherence and persistence in Appalachia, delineate the effects of access to care cancer on adherence/persistence, and evaluate the influences of adherence and persistence on overall survival.A retrospective cohort study from 2006 to 2008 was conducted among female breast cancer survivors living in the Appalachian counties of 4 states (PA, OH, KY, and NC). We linked cancer registries to Medicare claims data and included patients with invasive, nonmetastatic, hormone-receptor-positive breast cancer who received guideline-recommended AET. Medication adherence was defined as corresponding to a Medication Possession Ratio (MPR) ≥0.8 and logistic regression was utilized to assess predictors of adherence. Medication nonpersistence was defined as the discontinuation of drugs after exceeding a 60-day medication gap, and multivariate adjusted estimates of nonpersistence were obtained using the Cox proportional hazards (PH) model.About 31% of the total 428 patients were not adherent to AET, and 30% were not persistent over an average follow-up period of 421 days. Tamoxifen, relative to aromatase inhibitors, was associated with higher odds of adherence (odds ratio = 2.82, P < 0.001) and a lower risk of nonpersistence (hazard ratio = 0.40, P < 0.001). Drug-related side effects like pain may be an important factor leading to nonadherence and early discontinuation. In addition, aromatase inhibitor (AI) adherence and persistence were significantly influenced by out-of-pocket drug costs, dual eligibility status, and coverage gaps. Nonadherence to and nonpersistence with AET were associated with higher risks of all-cause mortality.Our findings

  6. Induction of tamoxifen resistance in breast cancer cells by ELF electromagnetic fields.

    PubMed

    Girgert, Rainer; Schimming, Hartmut; Körner, Wolfgang; Gründker, Carsten; Hanf, Volker

    2005-11-01

    The incidence of breast cancer in western societies has been rising ever since the Second World War. Besides the exposure to a multitude of new chemical compounds, electromagnetic field exposure has been linked to breast cancer through a radiation-mediated anti-melatonin pathway. We investigated, whether low-frequency electromagnetic field exposure interferes with the anti-estrogenic activity of tamoxifen. Two different clones of the breast cancer cell line MCF-7 were exposed to highly homogeneous 50Hz electromagnetic fields and IC(50) values were calculated from dose-response curves of tamoxifen at various field intensities. An intensity-dependent shift of tamoxifen dose-response curves to higher concentrations with a maximal response at 1.2muT was observed. Hypothetically, electromagnetic field exposure could contribute to tamoxifen resistance observed in breast cancer after long-term treatment.

  7. Induction of tamoxifen resistance in breast cancer cells by ELF electromagnetic fields

    SciTech Connect

    Girgert, Rainer . E-mail: rainer.girgert@med.uni-goettingen.de; Schimming, Hartmut; Koerner, Wolfgang; Gruendker, Carsten; Hanf, Volker

    2005-11-04

    The incidence of breast cancer in western societies has been rising ever since the Second World War. Besides the exposure to a multitude of new chemical compounds, electromagnetic field exposure has been linked to breast cancer through a radiation-mediated anti-melatonin pathway. We investigated, whether low-frequency electromagnetic field exposure interferes with the anti-estrogenic activity of tamoxifen. Two different clones of the breast cancer cell line MCF-7 were exposed to highly homogeneous 50 Hz electromagnetic fields and IC{sub 50} values were calculated from dose-response curves of tamoxifen at various field intensities. An intensity-dependent shift of tamoxifen dose-response curves to higher concentrations with a maximal response at 1.2 {mu}T was observed. Hypothetically, electromagnetic field exposure could contribute to tamoxifen resistance observed in breast cancer after long-term treatment.

  8. Colocalization of Estrogen Receptors with the Fluorescent Tamoxifen Derivative, FLTX1, Analyzed by Confocal Microscopy.

    PubMed

    Morales, Araceli; Marín, Raquel; Marrero-Alonso, Jorge; Boto, Alicia; Díaz, Mario

    2016-01-01

    Tamoxifen is a selective estrogen receptor modulator that competitively binds the ligand-binding domain of estrogen receptors. Binding of tamoxifen displaces its cognate ligand, 17β-estradiol, thereby hampering the activation of estrogen receptors. Cellular labeling of ER is typically carried out using specific antibodies which require permeabilization of cells, incubation with secondary antibodies, and are expensive and time consuming. In this article, we describe the usefulness of FLTX1, a novel fluorescent tamoxifen derivative, which allows the labeling of estrogen receptors in immunocytochemistry and immunohistochemistry studies, both under permeabilized and non-permeabilized conditions. Further, besides labeling canonical estrogen receptors, this novel fluorescent probe is also suitable for the identification of unconventional targets such membrane estrogen receptors as well as other noncanonical targets, some of which are likely responsible for the number of undesired side effects reported during long-term tamoxifen treatments. PMID:26585134

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

    SciTech Connect

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

    2009-06-01

    Tamoxifen-resistance is a major cause of death in patients with recurrent breast cancer. Current clinical factors can correctly predict therapy response in only half of the treated patients. Identification of proteins that associate with tamoxifen-resistance is a first step towards better response prediction and tailored treatment of patients. In the present study we intended to identify putative protein biomarkers indicative of tamoxifen therapy-resistance in breast cancer, using nanoLC coupled with FTICR MS. Comparative proteome analysis was performed on ~5,500 pooled tumor cells (corresponding to ~550 ng protein lysate/analysis) obtained through laser capture microdissection (LCM) from two independently processed data sets (n=24 and n=27) containing both tamoxifen therapy-sensitive and therapy-resistant tumors. Peptides and proteins were identified by matching mass and elution time of newly acquired LC-MS features to information in previously generated accurate mass and time tag (AMT) reference databases.

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

    Cancer.gov

    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.

  11. N-feruloylserotonin in preventive combination therapy with methotrexate reduced inflammation in adjuvant arthritis.

    PubMed

    Kuncirova, Viera; Ponist, Silvester; Mihalova, Danica; Drafi, Frantisek; Nosal, Radomir; Acquaviva, Alessandra; Gardi, Concetta; Harmatha, Juraj; Hradkova, Iveta; Bauerova, Katarina

    2014-12-01

    Many of disease-modifying anti-rheumatic drugs often have side effects at high doses and/or during long-term administration. Increased efficacy without increased toxicity is expected for combination therapy of rheumatoid arthritis (RA). The aim of the study was to examine the effect of N-feruloylserotonin (N-f-5HT) and methotrexate (MTX) in monotherapy and in combination therapy on disease progression and inflammation in arthritic rats. Adjuvant arthritis was induced by intradermal injection of Mycobacterium butyricum in incomplete Freund's adjuvant in Lewis rats. The experiment included healthy animals, arthritic animals without any drug administration, arthritic animals with administration of N-f-5HT in the oral daily dose of 15 mg/kg b.w., arthritic animals with administration of MTX in the oral dose of 0.3 mg/kg b.w. twice a week and arthritic animals treated with the combination of N-f-5HT and MTX. N-f-5HT in monotherapy reduced only activation of NF-κB and did not have any significant effect on other parameters monitored. Low-dose treatment of MTX decreased the level of IL-1β and MCP-1 on day 14 and activation of NF-κB in liver without significant effect on other parameters. N-f-5HT and MTX combination showed both the anti-arthritic (hind paw volume and arthritic score) and anti-inflammatory effect (plasmatic levels of IL-1β, IL-17, MCP-1, CRP, and activation of NF-κB in liver). In combination with MTX, N-f-5HT markedly potentiated the therapeutic effect of MTX low dose, which resulted in significant improvement of all parameters measured. The findings showed that the combination therapy simultaneously decreased multiple markers of inflammation, a result crucial for future therapy of RA.

  12. Novel off-target effect of tamoxifen--inhibition of acid ceramidase activity in cancer cells.

    PubMed

    Morad, Samy A F; Levin, Jonathan C; Tan, Su-Fern; Fox, Todd E; Feith, David J; Cabot, Myles C

    2013-12-01

    Acid ceramidase (AC), EC 3.5.1.23, a lysosomal enzyme, catalyzes the hydrolysis of ceramide to constituent sphingoid base, sphingosine, and fatty acid. Because AC regulates the levels of pro-apoptotic ceramide and mitogenic sphingosine-1-phosphate, it is considered an apt target in cancer therapy. The present study reveals, for the first time, that the prominent antiestrogen, tamoxifen, is a pan-effective AC inhibitor in the low, single digit micromolar range, as demonstrated in a wide spectrum of cancer cell types, prostate, pancreatic, colorectal, and breast. Prostate cancer cells were chosen for the detailed investigations. Treatment of intact PC-3 cells with tamoxifen produced time- and dose-dependent inhibition of AC activity. Tamoxifen did not impact cell viability nor did it inhibit AC activity in cell-free assays. In pursuit of mechanism of action, we demonstrate that tamoxifen induced time-, as early as 5min, and dose-dependent, as low as 5μM, increases in lysosomal membrane permeability (LMP), and time- and dose-dependent downregulation of AC protein expression. Assessing various protease inhibitors revealed that a cathepsin B inhibitor blocked tamoxifen-elicited downregulation of AC protein; however, this action failed to restore AC activity unless assayed in a cell-free system at pH4.5. In addition, pretreatment with tamoxifen inhibited PC-3 cell migration. Toremifene, an antiestrogen structurally similar to tamoxifen, was also a potent inhibitor of AC activity. This study reveals a new, off-target action of tamoxifen that may be of benefit to enhance anticancer therapies that either incorporate ceramide or target ceramide metabolism. PMID:23939396

  13. Assessment of Breast Cancer Patients' Knowledge and Decisional Conflict Regarding Tamoxifen Use.

    PubMed

    Kim, Se Ik; Lee, Yumi; Son, Yedong; Jun, So Yeun; Yun, Sooin; Bae, Hyo Sook; Lim, Myong Cheol; Jung, So-Youn; Joo, Jungnam; Lee, Eun Sook

    2015-11-01

    Breast cancer is the most common type of female cancer. Tamoxifen, a selective estrogen receptor modulator, is widely used to decrease breast cancer recurrence and mortality among patients. However, it also increases the risk of endometrial cancer. This study aimed to assess knowledge and decisional conflict regarding tamoxifen use. Between June and October 2014, breast cancer patients using tamoxifen were consecutively screened and requested to complete a survey including the EQ-5D, Satisfaction with Decision Scale (SWD), Decisional Conflict Scale (DCS), and a self-developed, 15-item questionnaire measuring tamoxifen-related knowledge. The study sample comprised 299 patients. The mean total knowledge score was 63.4 of a possible 100.0 (range, 13.3-93.3). While 73.9% of the participants knew that tamoxifen reduces the risk of breast cancer recurrence, only 57.9% knew that the drug increases endometrial cancer risk. A higher education level (≥ college) was associated with a higher, total knowledge score (β = 4.291; P = 0.017). A higher knowledge score was associated with a decreased DCS score (β = -0.366; P < 0.001). A higher SWD score was also associated with decreased decisional conflict (β = -0.178; P < 0.001). In conclusion, the breast cancer patients with higher levels of tamoxifen-related knowledge showed lower levels of decisional conflict regarding tamoxifen use. Clinicians should provide the exact information about tamoxifen treatment to patients, based on knowledge assessment results, so as to aid patients' decision-making with minimal conflict. PMID:26539004

  14. Tamoxifen Ameliorates Peritoneal Membrane Damage by Blocking Mesothelial to Mesenchymal Transition in Peritoneal Dialysis

    PubMed Central

    del Peso, Gloria; Gónzalez-Mateo, Guadalupe; Fernández-Millara, Vanessa; Santamaria, Beatríz; Bajo, Maria Auxiliadora; Sánchez-Tomero, José Antonio; Guerra-Azcona, Gonzalo; Selgas, Rafael; López-Cabrera, Manuel; Aguilera, Abelardo I.

    2013-01-01

    Mesothelial-to-mesenchymal transition (MMT) is an auto-regulated physiological process of tissue repair that in uncontrolled conditions such as peritoneal dialysis (PD) can lead to peritoneal fibrosis. The maximum expression of peritoneal fibrosis induced by PD fluids and other peritoneal processes is the encapsulating peritoneal sclerosis (EPS) for which no specific treatment exists. Tamoxifen, a synthetic estrogen, has successfully been used to treat retroperitoneal fibrosis and EPS associated with PD. Hence, we used in vitro and animal model approaches to evaluate the efficacy of Tamoxifen to inhibit the MMT as a trigger of peritoneal fibrosis. In vitro studies were carried out using omentum-derived mesothelial cells (MCs) and effluent-derived MCs. Tamoxifen blocked the MMT induced by transforming growth factor (TGF)-β1, as it preserved the expression of E-cadherin and reduced the expression of mesenchymal-associated molecules such as snail, fibronectin, collagen-I, α-smooth muscle actin, and matrix metalloproteinse-2. Tamoxifen-treatment preserved the fibrinolytic capacity of MCs treated with TGF-β1 and decreased their migration capacity. Tamoxifen did not reverse the MMT of non-epitheliod MCs from effluents, but it reduced the expression of some mesenchymal molecules. In mice PD model, we demonstrated that MMT progressed in parallel with peritoneal membrane thickness. In addition, we observed that Tamoxifen significantly reduced peritoneal thickness, angiogenesis, invasion of the compact zone by mesenchymal MCs and improved peritoneal function. Tamoxifen also reduced the effluent levels of vascular endothelial growth factor and leptin. These results demonstrate that Tamoxifen is a therapeutic option to treat peritoneal fibrosis, and that its protective effect is mediated via modulation of the MMT process. PMID:23637793

  15. ESR1 mutations affect anti-proliferative responses to tamoxifen through enhanced cross-talk with IGF signaling.

    PubMed

    Gelsomino, Luca; Gu, Guowei; Rechoum, Yassine; Beyer, Amanda R; Pejerrey, Sasha M; Tsimelzon, Anna; Wang, Tao; Huffman, Kenneth; Ludlow, Andrew; Andò, Sebastiano; Fuqua, Suzanne A W

    2016-06-01

    The purpose of this study was to address the role of ESR1 hormone-binding mutations in breast cancer. Soft agar anchorage-independent growth assay, Western blot, ERE reporter transactivation assay, proximity ligation assay (PLA), coimmunoprecipitation assay, silencing assay, digital droplet PCR (ddPCR), Kaplan-Meier analysis, and statistical analysis. It is now generally accepted that estrogen receptor (ESR1) mutations occur frequently in metastatic breast cancers; however, we do not yet know how to best treat these patients. We have modeled the three most frequent hormone-binding ESR1 (HBD-ESR1) mutations (Y537N, Y537S, and D538G) using stable lentiviral transduction in human breast cancer cell lines. Effects on growth were examined in response to hormonal and targeted agents, and mutation-specific changes were studied using microarray and Western blot analysis. We determined that the HBD-ESR1 mutations alter anti-proliferative effects to tamoxifen (Tam), due to cell-intrinsic changes in activation of the insulin-like growth factor receptor (IGF1R) signaling pathway and levels of PIK3R1/PIK3R3. The selective estrogen receptor degrader, fulvestrant, significantly reduced the anchorage-independent growth of ESR1 mutant-expressing cells, while combination treatments with the mTOR inhibitor everolimus, or an inhibitor blocking IGF1R, and the insulin receptor significantly enhanced anti-proliferative responses. Using digital drop (dd) PCR, we identified mutations at high frequencies ranging from 12 % for Y537N, 5 % for Y537S, and 2 % for D538G in archived primary breast tumors from women treated with adjuvant mono-tamoxifen therapy. The HBD-ESR1 mutations were not associated with recurrence-free or overall survival in response in this patient cohort and suggest that knowledge of other cell-intrinsic factors in combination with ESR1 mutation status will be needed determine anti-proliferative responses to Tam. PMID:27178332

  16. Tamoxifen-model membrane interactions: an FT-IR study

    NASA Astrophysics Data System (ADS)

    Boyar, Handan; Severcan, Feride

    1997-06-01

    The temperature- and concentration-induced effects of tamoxifen (TAM) on dipalmitoyl phosphatidylcholine (DPPC) model membranes were investigated by the Fourier transform-infrared (FT-IR) spectroscopic technique. An investigation of the C-H stretching region and the CO mode reveals that the inclusion of TAM changes the physical properties of the DPPC multibilayers by (i) shifting the main phase transition to lower temperatures; (ii) broadening the transition profile slightly; (iii) disordering the system in the gel and in the liquid crystalline phases; (iv) increasing the dynamics in the gel phase and decreasing the dynamics of the acyl chains in the liquid crystalline phase; (v) increasing the mobility of the terminal methyl group region of the bilayer in the gel phase and decreasing it in the liquid crystalline phase; (vi) increasing the frequency of the CO stretching mode both in the gel and in the liquid crystalline phases, i.e. non-bonding with carbonyl groups.

  17. Longitudinal Assessment of Cognitive Changes Associated With Adjuvant Treatment for Breast Cancer: Impact of Age and Cognitive Reserve

    PubMed Central

    Ahles, Tim A.; Saykin, Andrew J.; McDonald, Brenna C.; Li, Yuelin; Furstenberg, Charlotte T.; Hanscom, Brett S.; Mulrooney, Tamsin J.; Schwartz, Gary N.; Kaufman, Peter A.

    2010-01-01

    Purpose To examine the impact of age and cognitive reserve on cognitive functioning in patients with breast cancer who are receiving adjuvant treatments. Patients and Methods Patients with breast cancer exposed to chemotherapy (n = 60; mean age, 51.7 years) were evaluated with a battery of neuropsychological and psychological tests before treatment and at 1, 6, and 18 months after treatment. Patients not exposed to chemotherapy (n = 72; mean age, 56.6 years) and healthy controls (n = 45; mean age, 52.9 years) were assessed at matched intervals. Results Mixed-effects modeling revealed significant effects for the Processing Speed and Verbal Ability domains. For Processing Speed, a three-way interaction among treatment group, age, and baseline cognitive reserve (P < .001) revealed that older patients with lower baseline cognitive reserve who were exposed to chemotherapy had lower performance on Processing Speed compared with patients not exposed to chemotherapy (P = .003) and controls (P < .001). A significant group by time interaction for Verbal Ability (P = .01) suggested that the healthy controls and no chemotherapy groups improved over time. The chemotherapy group failed to improve at 1 month after treatment but improved during the last two follow-up assessments. Exploratory analyses suggested a negative effect of tamoxifen on Processing Speed (P = .036) and Verbal Memory (P = .05) in the no-chemotherapy group. Conclusion These data demonstrated that age and pretreatment cognitive reserve were related to post-treatment decline in Processing Speed in women exposed to chemotherapy and that chemotherapy had a short-term impact on Verbal Ability. Exploratory analysis of the impact of tamoxifen suggests that this pattern of results may be due to a combination of chemotherapy and tamoxifen. PMID:20837957

  18. Integrative Analysis of Response to Tamoxifen Treatment in ER-Positive Breast Cancer Using GWAS Information and Transcription Profiling

    PubMed Central

    Hicks, Chindo; Kumar, Ranjit; Pannuti, Antonio; Miele, Lucio

    2012-01-01

    Variable response and resistance to tamoxifen treatment in breast cancer patients remains a major clinical problem. To determine whether genes and biological pathways containing SNPs associated with risk for breast cancer are dysregulated in response to tamoxifen treatment, we performed analysis combining information from 43 genome-wide association studies with gene expression data from 298 ER+ breast cancer patients treated with tamoxifen and 125 ER+ controls. We identified 95 genes which distinguished tamoxifen treated patients from controls. Additionally, we identified 54 genes which stratified tamoxifen treated patients into two distinct groups. We identified biological pathways containing SNPs associated with risk for breast cancer, which were dysregulated in response to tamoxifen treatment. Key pathways identified included the apoptosis, P53, NFkB, DNA repair and cell cycle pathways. Combining GWAS with transcription profiling provides a unified approach for associating GWAS findings with response to drug treatment and identification of potential drug targets. PMID:22399860

  19. Fourteenth Gaddum Memorial Lecture. A current view of tamoxifen for the treatment and prevention of breast cancer.

    PubMed Central

    Jordan, V. C.

    1993-01-01

    Tamoxifen has been found to be a safe and effective treatment for all stages of breast cancer. Long term tamoxifen therapy is associated with some rare, but potentially serious, side effects so patients should be carefully monitored. However, long term tamoxifen therapy is also associated with a number of physiological benefits over and above its tumouristatic action. These benefits include a decrease in the development of contralateral breast cancer, the maintenance of bone density in postmenopausal women and a decrease in cardiovascular disease. The successful application of tamoxifen to treat breast cancer has increased enthusiasm to test its worth to prevent breast cancer. Although there are individual requests by patients for tamoxifen to prevent breast cancer, individual treatment is inappropriate. Tamoxifen can only be adequately evaluated as a preventive in randomized, double-blind clinical trials. These trials are in place and physicians should encourage women to participate and establish a new therapeutic option as rapidly as possible. PMID:8242225

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

    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.

  2. Tamoxifen Regulates Cell Fate Through Mitochondrial Estrogen Receptor Beta in Breast Cancer

    PubMed Central

    Razandi, Mahnaz; Pedram, Ali; Jordan, V Craig; Fuqua, Suzanne; Levin, Ellis R

    2012-01-01

    Tamoxifen has both cytostatic and cytotoxic properties for breast cancer. Tamoxifen engaged mitochondrial estrogen receptor beta (ERβ) as an antagonist in MCF-7 BK cells, increasing reactive oxygen species (ROS) concentrations from the mitochondria that were required for cytotoxicity. In part this derived from tamoxifen down-regulating manganese superoxide dismutase (MnSOD) activity through nitrosylating tyrosine 34, thereby increasing ROS. ROS activated protein kinase C delta and c-jun N-terminal kinases, resulting in the mitochondrial translocation of Bax and cytochrome C release. Interestingly, tamoxifen failed to cause high ROS levels or induce cell death in MCF7BK-TR cells due to stimulation of MnSOD activity through agonistic effects at mitochondrial ERβ. In several mouse xenograft models, lentiviral shRNA-induced knockdown of MnSOD caused tumors that grew in the presence of tamoxifen to undergo substantial apoptosis. Tumor MnSOD and mitochondrial ERβ are therefore targets for therapeutic intervention to reverse tamoxifen resistance and enhance a cell death response. PMID:22907432

  3. Combination effects of tamoxifen plus 5-fluorouracil on gastric cancer cell lines in vitro.

    PubMed

    Hosoya, Y; Kitoh, Y; Kobayashi, E; Okabe, R; Fujimura, A; Kanazawa, K

    1999-06-01

    We tested the effect of tamoxifen alone and tamoxifen plus 5-fluorouracil (5-FU) on proliferation of two different types of gastric cancer cell lines using the WST-1 method. A high dose of tamoxifen suppressed the proliferation of KATOIII cells (poorly differentiated adenocarcinoma), but MKN28 cells (well-differentiated adenocarcinoma) were not affected. The combination of the two drugs resulted in a synergistic anti-proliferative activity on KATOIII cells. On the other hand, in the combination therapy, tamoxifen stimulated MKN28 cells to proliferate in a dose-dependent manner. TGF-beta1 secretion was not changed in KATOIII cells by tamoxifen plus 5-FU treatment but was down-regulated in MKN28 cells. Both cancer cell lines were judged as intracellular estrogen receptor (ER) negative. These data suggest that the anti-proliferative effects of tamoxifen plus 5-FU on KATOIII cells were not dependent on ER expression or TGF-beta1 secretion. On the other hand, their proliferative effects on MKN28 cells might be, in part, caused by the reduced secretion of TGF-beta1. PMID:10403552

  4. MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

    PubMed Central

    Mohseni, Morassa; Cidado, Justin; Croessmann, Sarah; Cravero, Karen; Cimino-Mathews, Ashley; Wong, Hong Yuen; Scharpf, Rob; Zabransky, Daniel J.; Abukhdeir, Abde M.; Garay, Joseph P.; Wang, Grace M.; Beaver, Julia A.; Cochran, Rory L.; Blair, Brian G.; Rosen, D. Marc; Erlanger, Bracha; Argani, Pedram; Hurley, Paula J.; Lauring, Josh; Park, Ben Ho

    2014-01-01

    Tamoxifen is effective for treating estrogen receptor-alpha (ER) positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. Here we describe a previously unidentified gene, MACROD2 that confers tamoxifen resistance and estrogen independent growth. We found MACROD2 is amplified and overexpressed in metastatic tamoxifen-resistant tumors. Transgene overexpression of MACROD2 in breast cancer cell lines results in tamoxifen resistance, whereas RNAi-mediated gene knock down reverses this phenotype. MACROD2 overexpression also leads to estrogen independent growth in xenograft assays. Mechanistically, MACROD2 increases p300 binding to estrogen response elements in a subset of ER regulated genes. Primary breast cancers and matched metastases demonstrate MACROD2 expression can change with disease evolution, and increased expression and amplification of MACROD2 in primary tumors is associated with worse overall survival. These studies establish MACROD2 as a key mediator of estrogen independent growth and tamoxifen resistance, as well as a potential novel target for diagnostics and therapy. PMID:25422431

  5. Cytotoxic Activities of Silver Nanoparticles and Silver Ions in Parent and Tamoxifen-Resistant T47D Human Breast Cancer Cells and Their Combination Effects with Tamoxifen against Resistant Cells.

    PubMed

    Ostad, Seyed Naser; Dehnad, Shahrzad; Nazari, Zeinab Esmail; Fini, Shohreh Tavajohi; Mokhtari, Narges; Shakibaie, Mojtaba; Shahverdi, Ahmad Reza

    2010-10-01

    Studies on biomedical applications of nanoparticles are growing with a rapid pace. In medicine, nanoparticles may be the solution for multi-drug-resistance which is still a major drawback in chemotherapy of cancer. In the present study, we investigated the potential cytotoxic effect of silver nanoparticles (Ag NPs) and silver ions (Ag(+)) in both parent and tamoxifen-resistant T47D cells in presence and absence of tamoxifen. Ag NPs were synthesized (< 28 nm) and MTT assay was carried out. The associated IC(50) values were found to be: 6.31 µg/ml for Ag NPs/parent cells, 37.06 µg/ml for Ag NPs/tamoxifen-resistant cells, 33.06 µg/ml for Ag(+)/parent cells and 10.10 µg/ml for Ag(+)/resistant cells. As a separate experiment, the effect of subinhibitory concentrations of Ag NPs and Ag(+) on the proliferation of tamoxifen-resistant cells was evaluated at non-toxic concentrations of tamoxifen. Our results suggested that in non-cytotoxic concentrations of silver nanomaterials and tamoxifen, the combinations of Ag(+)-tamoxifen and Ag NPs-tamoxifen are still cytotoxic. This finding may be of great potential benefit in chemotherapy of breast cancer; since much lower doses of tamoxifen may be needed to produce the same cytotoxic effect and side effects will be reduced. PMID:23408729

  6. Cytotoxic Activities of Silver Nanoparticles and Silver Ions in Parent and Tamoxifen-Resistant T47D Human Breast Cancer Cells and Their Combination Effects with Tamoxifen against Resistant Cells

    PubMed Central

    Ostad, Seyed Naser; Dehnad, Shahrzad; Nazari, Zeinab Esmail; Fini, Shohreh Tavajohi; Mokhtari, Narges; Shakibaie, Mojtaba; Shahverdi, Ahmad Reza

    2010-01-01

    Studies on biomedical applications of nanoparticles are growing with a rapid pace. In medicine, nanoparticles may be the solution for multi-drug-resistance which is still a major drawback in chemotherapy of cancer. In the present study, we investigated the potential cytotoxic effect of silver nanoparticles (Ag NPs) and silver ions (Ag+) in both parent and tamoxifen-resistant T47D cells in presence and absence of tamoxifen. Ag NPs were synthesized (< 28 nm) and MTT assay was carried out. The associated IC50 values were found to be: 6.31 µg/ml for Ag NPs/parent cells, 37.06 µg/ml for Ag NPs/tamoxifen-resistant cells, 33.06 µg/ml for Ag+/parent cells and 10.10 µg/ml for Ag+/resistant cells. As a separate experiment, the effect of subinhibitory concentrations of Ag NPs and Ag+ on the proliferation of tamoxifen-resistant cells was evaluated at non-toxic concentrations of tamoxifen. Our results suggested that in non-cytotoxic concentrations of silver nanomaterials and tamoxifen, the combinations of Ag+-tamoxifen and Ag NPs-tamoxifen are still cytotoxic. This finding may be of great potential benefit in chemotherapy of breast cancer; since much lower doses of tamoxifen may be needed to produce the same cytotoxic effect and side effects will be reduced. PMID:23408729

  7. Effect of tamoxifen and transdermal hormone replacement therapy on cardiovascular risk factors in a prevention trial. Italian Chemoprevention Group.

    PubMed Central

    Decensi, A.; Robertson, C.; Rotmensz, N.; Severi, G.; Maisonneuve, P.; Sacchini, V.; Boyle, P.; Costa, A.; Veronesi, U.

    1998-01-01

    The combination of tamoxifen and transdermal hormone replacement therapy (HRT) may potentially reduce risks and side-effects of either agent, but an adverse interaction could attenuate their beneficial effects. We assessed the effects of their combination on cardiovascular risk factors within a prevention trial of tamoxifen. Baseline and 12-month measurements of total, low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol, platelets and white blood cells were obtained in the following four groups: tamoxifen (n = 1117), placebo (n = 1112), tamoxifen and HRT (n = 68), placebo and HRT (n = 87). The analysis was further extended to women who were on HRT at randomization but discontinued it during the 12-month intervention period (n = 33 on tamoxifen and n = 35 on placebo) and to women who were not on HRT but started it during intervention (n = 36 in both arms of the study). Compared with small changes in the placebo group, tamoxifen was associated with changes in total, LDL- and HDL-cholesterol of approximately -9%, -19% and +0.2% in continuous HRT users compared with -9%, -14% and -0.8% in never HRT users. Similarly, there was no interaction on platelet count. In contrast, the decrease in total and LDL-cholesterol levels induced by tamoxifen was blunted by two-thirds in women who started HRT while on tamoxifen (P = 0.051 for the interaction term). We conclude that the beneficial effects of tamoxifen on cardiovascular risk factors are unchanged in current HRT users, whereas they may be attenuated in women who start transdermal HRT while on tamoxifen. Whereas a trial of tamoxifen in women already on transdermal HRT is warranted, prescription of HRT during tamoxifen may attenuate its activity. PMID:9744493

  8. Lecithin/chitosan controlled release nanopreparations of tamoxifen citrate: loading, enzyme-trigger release and cell uptake.

    PubMed

    Barbieri, Stefano; Sonvico, Fabio; Como, Caterina; Colombo, Gaia; Zani, Franca; Buttini, Francesca; Bettini, Ruggero; Rossi, Alessandra; Colombo, Paolo

    2013-05-10

    Tamoxifen citrate (TAM), an anticancer drug with amphiphilic properties, was loaded in lecithin/chitosan nanoparticles (LCN) with a view to oral administration. The influence of tamoxifen loading on the physico-chemical properties of nanoparticles was studied. Size, surface charge and morphological properties of tamoxifen-loaded nanoparticles (LCN-TAM) were assessed. The increase in the tamoxifen amount in the LCN-TAM preparation up to 60 mg/100 ml maintained the positive zeta potential value of about +45 mV. A statistically significant decrease in particle size was observed for TAM amounts between 5 and 20mg. A strong influence of loaded tamoxifen on the structure of lecithin/chitosan nanoparticles was observed, supported by the quantification of free chitosan and morphological analysis. A loading of tamoxifen in nanoparticles of around 19% was obtained. The release of the drug from the LCN-TAM colloidal dispersion was measured, showing that tamoxifen citrate was released very slowly in simulated gastro-intestinal fluids without enzymes. When enzymes able to dismantle the nanoparticle structure were added to the dissolution medium, drug release was triggered and continued in a prolonged manner. Tamoxifen-loaded nanoparticles showed cytotoxicity towards MCF-7 cells comparable to that obtained with tamoxifen citrate solution, but the rate of this toxic effect was dependent on drug release. Caco-2 cells, used as a model of the intestinal epithelium, were shown to take up the TAM loaded nanoparticles extensively. PMID:23428841

  9. Ex vivo permeation of tamoxifen and its 4-OH metabolite through rat intestine from lecithin/chitosan nanoparticles.

    PubMed

    Barbieri, S; Buttini, F; Rossi, A; Bettini, R; Colombo, P; Ponchel, G; Sonvico, F; Colombo, G

    2015-08-01

    Tamoxifen citrate is an anticancer drug slightly soluble in water. Administered orally, it shows great intra- and inter-patient variations in bioavailability. We developed a nanoformulation based on phospholipid and chitosan able to efficiently load tamoxifen and showing an enzyme triggered release. In this work the permeation of tamoxifen released from lecithin/chitosan nanoparticles across excised rat intestinal wall mounted in an Ussing chamber was investigated. Compared to tamoxifen citrate suspension, the amount of the drug permeated using the nanoformulation was increased from 1.5 to 90 times, in absence or in presence of pancreatin or lipase, respectively. It was also evidenced the formation of an active metabolite of tamoxifen, 4-hydroxy tamoxifen, however, the amount of metabolite permeated remained roughly constant in all experiments. The effect of enzymes on intestinal permeation of tamoxifen was shown only when tamoxifen-loaded nanoparticles were in intimate contact with the mucosal surface. The encapsulation of tamoxifen in lecithin/chitosan nanoparticles improved the non-metabolized drug passing through the rat intestinal tissue via paracellular transport. PMID:26095916

  10. Preferential pi-pi complexation between tamoxifen and borage oil/gamma linolenic acid: transcutaneous delivery and NMR spectral modulation.

    PubMed

    Heard, Charles M; Gallagher, Simon J; Congiatu, Costantino; Harwood, John; Thomas, Christopher P; McGuigan, Christopher; Nemcová, Marta; Nouskova, Tereza

    2005-09-30

    The effect of different proportions of borage oil on the in vitro transcutaneous delivery of tamoxifen were studied, with the aim of developing a gel capable of the simultaneous delivery of tamoxifen and gamma linolenic acid across (breast) skin. Supplementary work probed 1H NMR spectral data for tamoxifen in the presence of different proportions of polyunsaturated or unsaturated fatty acids. Typical, non-aqueous gels were modified to contain 1% tamoxifen and three levels of borage oil ( approximately 25% gamma linolenic acid) and the transcutaneous delivery of both tamoxifen and GLA across full thickness skin determined in vitro. Both tamoxifen and gamma linolenic acid permeated the skin with the ratio of moles being consistent at approximately 4:1. This was irrespective of time, amount of borage oil contained in the formulation (above a minimum) and the presence of other (unsaturated) excipients: mineral oil, Miglyiol 810N, white soft paraffin, PEG400 and Cabosil M5. Dose-dependent downfield shifts of tamoxifen aromatic protons were observed in the presence of borage oil and linolenic acid (gamma and alpha), but not saturated triacyl glycerol. The permeation data suggested vehicular complexation between tamoxifen and polyunsaturated constituents of borage oil and that such complexes permeated the skin intact. The 1H NMR data supported the hypothesis that such complexation was a consequence of preferential pi-pi orbital interactions between the phenyl groups of tamoxifen and the multiple double bonds of GLA. The mechanism for the permeation of intact complexes across skin remains to be elucidated.

  11. Effects of monotherapy and polytherapy on the blink reflex in epileptic patients.

    PubMed

    Lancman, M E; Cristiano, E; Golimstok, A; Granillo, R J

    1993-01-01

    We performed the blink reflex (BR) in 20 normal volunteers, 13 epileptic patients receiving antiepileptic drug (AED) monotherapy, and 13 epileptic patients receiving AED polytherapy. Comparison of R1, ipsilateral and contralateral R2 and VIIth nerve latencies in the three groups showed no statistically significant differences R1 and VIIth nerve latencies among the three groups. There were statistically significant differences between the polytherapy group and the monotherapy and control groups in comparisons of ipsilateral and contralateral R2. There were no significant differences between the monotherapy group and the control group for ipsilateral and contralateral R2. We hypothesized that AED polytherapy might interfere with synaptic transmission in the polysynaptic pathway of the blink reflex, prolonging the latency of R2. These results provide further evidence of the pathophysiologic effects associated with polytherapy in epileptic patients.

  12. Adjuvants: Classification, Modus Operandi, and Licensing

    PubMed Central

    Apostólico, Juliana de Souza

    2016-01-01

    Vaccination is one of the most efficient strategies for the prevention of infectious diseases. Although safer, subunit vaccines are poorly immunogenic and for this reason the use of adjuvants is strongly recommended. Since their discovery in the beginning of the 20th century, adjuvants have been used to improve immune responses that ultimately lead to protection against disease. The choice of the adjuvant is of utmost importance as it can stimulate protective immunity. Their mechanisms of action have now been revealed. Our increasing understanding of the immune system, and of correlates of protection, is helping in the development of new vaccine formulations for global infections. Nevertheless, few adjuvants are licensed for human vaccines and several formulations are now being evaluated in clinical trials. In this review, we briefly describe the most well known adjuvants used in experimental and clinical settings based on their main mechanisms of action and also highlight the requirements for licensing new vaccine formulations. PMID:27274998

  13. Vaccine adjuvants: putting innate immunity to work.

    PubMed

    Coffman, Robert L; Sher, Alan; Seder, Robert A

    2010-10-29

    Adjuvants enhance immunity to vaccines and experimental antigens by a variety of mechanisms. In the past decade, many receptors and signaling pathways in the innate immune system have been defined and these innate responses strongly influence the adaptive immune response. The focus of this review is to delineate the innate mechanisms by which adjuvants mediate their effects. We highlight how adjuvants can be used to influence the magnitude and alter the quality of the adaptive response in order to provide maximum protection against specific pathogens. Despite the impressive success of currently approved adjuvants for generating immunity to viral and bacterial infections, there remains a need for improved adjuvants that enhance protective antibody responses, especially in populations that respond poorly to current vaccines. However, the larger challenge is to develop vaccines that generate strong T cell immunity with purified or recombinant vaccine antigens.

  14. [Evaluation of the effectiveness of monotherapy in the treatment of epilepsy].

    PubMed

    Brignolio, F; Verzè, L; Baruchello, M

    1991-12-01

    On 44 patients undergoing monotherapy, with total plasma levels of drug therapeutic range, 33 had a reduction of the frequency of seizures, while the remaining 11 were unmodified. There was 90% improvement in Primary Generalized seizures, 73% in Secondary Generalized and 62% in Partial Complex; 27% of PC, 16% of PG and 16% of SG shifted to polytherapy. Considering that monotherapy can be better managed and is less toxic, we can recommend it as first choice treatment in newcomers, as a maintenance therapy, and as treatment of choice for the gradual elimination of therapy.

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

    SciTech Connect

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

    2014-04-18

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

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

    PubMed

    Borgo, M V; Lopes, A B; Gouvêa, S A; Romero, W G; Moyses, M R; Bissoli, N S; Abreu, G R

    2011-08-01

    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.

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

    PubMed

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

    2016-04-01

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

  18. Estrogen, tamoxifen, and Akt modulate expression of putative housekeeping genes in breast cancer cells.

    PubMed

    Shah, Khyati N; Faridi, Jesika S

    2011-07-01

    Clinically, Akt overexpression has been associated with tamoxifen resistance, and multiple in vitro breast cancer models of tamoxifen resistance have been developed. In order to study the mechanism of this tamoxifen resistance, differential gene expression studies have been performed utilizing quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Since accurate data normalization requires the use of a stable reference gene, the goal of this study was to identify the most stable reference gene for RT-qPCR (from a panel of putative housekeeping genes) that remains unaltered despite estrogen or tamoxifen treatment or stable overexpression of active Akt. Gene expression of nine candidate genes was determined in parental and Akt overexpressing MCF-7 breast cancer cells treated with estrogen, tamoxifen, or vehicle, and gene stability was analyzed using two different statistical models. Based on our results, we suggest RPL13A as suitable internal reference gene that is both stable and remains unaltered in MCF-7 cells regardless of estrogen or tamoxifen treatment or Akt overexpression. We also validated that expression levels for RPL13A, as well as RPLP0 (another member of the RPL protein family), remain unaltered after estrogen and tamoxifen treatment in the ER positive ZR-75-1 cell line and ER negative MDA-MB-468 breast cancer cell line. Both RPL13A and RPLP0 levels were also stable in normal and tumor mammary tissue from Her2 overexpressing mice. In addition, our work emphasizes the importance of a preliminary study to validate each reference gene that will be used for RT-qPCR.

  19. Profile of differentially expressed intratumoral cytokines to predict the immune-polarizing side effects of tamoxifen in breast cancer treatment

    PubMed Central

    Li, Bailiang; Li, Yang; Wang, Xiao-Yu; Yan, Zi-Qiao; Liu, Huidi; Liu, Gui-Rong; Liu, Shu-Lin

    2015-01-01

    Factors within the tissue of breast cancer (BC) may shift the polarization of CD4+ T cells towards Th2 direction. This tendency can promote tumor development and be enhanced by the use of tamoxifen during the treatment. Thus, the patients with low levels of tumor-induced Th2 polarization prior to tamoxifen treatment may better endure the immune-polarizing side effects (IPSE) of tamoxifen and have better prognoses. Estimation of Th2 polarization status should help predict the IPSE among tamoxifen-treated patients and guide the use of tamoxifen among all BC patients before the tamoxifen therapy. Here, we report profiling of differentially expressed (DE) intratumoral cytokines as a signature to evaluate the IPSE of tamoxifen. The DE genes of intratumoral CD4+ T cells (CD4 DEGs) were identified by gene expression profiles of purified CD4+ T cells from BC patients and validated by profiling of cultured intratumoral CD4+ T cells. Functional enrichment analyses showed a directed Th2 polarization of intratumoral CD4+ T cells. To find the factors inducing the Th2 polarization of CD4+ T cells, we identified 995 common DE genes of bulk BC tissues (BC DEGs) by integrating five independent datasets. Five DE cytokines observed in bulk BC tissues with dysregulated receptors in the intratumoral CD4+ T cells were selected as the predictor of the IPSE of tamoxifen. The patients predicted to suffer low IPSE (low Th2 polarization) had a significantly lower distant relapse risk than the patients predicted to suffer high IPSE in independent datasets (n = 608; HR = 4.326, P = 0.000897; HR = 2.014, P = 0.0173; HR = 2.72, P = 0.04077). Patients predicted to suffer low IPSE would benefit from tamoxifen treatment (HR = 2.908, P = 0.03905). The DE intratumoral cytokines identified in this study may help predict the IPSE of tamoxifen and justify the use of tamoxifen in BC treatment. PMID:25973310

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

    PubMed Central

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

    2013-01-01

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

  1. Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures.

    PubMed

    Oh, Djin-Ye; Dowling, David J; Ahmed, Saima; Choi, Hyungwon; Brightman, Spencer; Bergelson, Ilana; Berger, Sebastian T; Sauld, John F; Pettengill, Matthew; Kho, Alvin T; Pollack, Henry J; Steen, Hanno; Levy, Ofer

    2016-06-01

    Adjuvants boost vaccine responses, enhancing protective immunity against infections that are most common among the very young. Many adjuvants activate innate immunity, some via Toll-Like Receptors (TLRs), whose activities varies with age. Accordingly, characterization of age-specific adjuvant-induced immune responses may inform rational adjuvant design targeting vulnerable populations. In this study, we employed proteomics to characterize the adjuvant-induced changes of secretomes from human newborn and adult monocytes in response to Alum, the most commonly used adjuvant in licensed vaccines; Monophosphoryl Lipid A (MPLA), a TLR4-activating adjuvant component of a licensed Human Papilloma Virus vaccine; and R848 an imidazoquinoline TLR7/8 agonist that is a candidate adjuvant for early life vaccines. Monocytes were incubated in vitro for 24 h with vehicle, Alum, MPLA, or R848 and supernatants collected for proteomic analysis employing liquid chromatography-mass spectrometry (LC-MS) (data available via ProteomeXchange, ID PXD003534). 1894 non-redundant proteins were identified, of which ∼30 - 40% were common to all treatment conditions and ∼5% were treatment-specific. Adjuvant-stimulated secretome profiles, as identified by cluster analyses of over-represented proteins, varied with age and adjuvant type. Adjuvants, especially Alum, activated multiple innate immune pathways as assessed by functional enrichment analyses. Release of lactoferrin, pentraxin 3, and matrix metalloproteinase-9 was confirmed in newborn and adult whole blood and blood monocytes stimulated with adjuvants alone or adjuvanted licensed vaccines with distinct clinical reactogenicity profiles. MPLA-induced adult monocyte secretome profiles correlated in silico with transcriptome profiles induced in adults immunized with the MPLA-adjuvanted RTS,S malaria vaccine (Mosquirix™). Overall, adjuvants such as Alum, MPLA and R848 give rise to distinct and age-specific monocyte secretome profiles

  2. Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures*

    PubMed Central

    Oh, Djin-Ye; Dowling, David J.; Ahmed, Saima; Choi, Hyungwon; Brightman, Spencer; Bergelson, Ilana; Berger, Sebastian T.; Sauld, John F.; Pettengill, Matthew; Kho, Alvin T.; Pollack, Henry J.; Steen, Hanno; Levy, Ofer

    2016-01-01

    Adjuvants boost vaccine responses, enhancing protective immunity against infections that are most common among the very young. Many adjuvants activate innate immunity, some via Toll-Like Receptors (TLRs), whose activities varies with age. Accordingly, characterization of age-specific adjuvant-induced immune responses may inform rational adjuvant design targeting vulnerable populations. In this study, we employed proteomics to characterize the adjuvant-induced changes of secretomes from human newborn and adult monocytes in response to Alum, the most commonly used adjuvant in licensed vaccines; Monophosphoryl Lipid A (MPLA), a TLR4-activating adjuvant component of a licensed Human Papilloma Virus vaccine; and R848 an imidazoquinoline TLR7/8 agonist that is a candidate adjuvant for early life vaccines. Monocytes were incubated in vitro for 24 h with vehicle, Alum, MPLA, or R848 and supernatants collected for proteomic analysis employing liquid chromatography-mass spectrometry (LC-MS) (data available via ProteomeXchange, ID PXD003534). 1894 non-redundant proteins were identified, of which ∼30 - 40% were common to all treatment conditions and ∼5% were treatment-specific. Adjuvant-stimulated secretome profiles, as identified by cluster analyses of over-represented proteins, varied with age and adjuvant type. Adjuvants, especially Alum, activated multiple innate immune pathways as assessed by functional enrichment analyses. Release of lactoferrin, pentraxin 3, and matrix metalloproteinase-9 was confirmed in newborn and adult whole blood and blood monocytes stimulated with adjuvants alone or adjuvanted licensed vaccines with distinct clinical reactogenicity profiles. MPLA-induced adult monocyte secretome profiles correlated in silico with transcriptome profiles induced in adults immunized with the MPLA-adjuvanted RTS,S malaria vaccine (Mosquirix™). Overall, adjuvants such as Alum, MPLA and R848 give rise to distinct and age-specific monocyte secretome profiles

  3. A hard pill to swallow: a qualitative study of women's experiences of adjuvant endocrine therapy for breast cancer

    PubMed Central

    Harrow, Alison; Dryden, Ruth; McCowan, Colin; Radley, Andrew; Parsons, Mark; Thompson, Alastair M; Wells, Mary

    2014-01-01

    Objective To explore women's experiences of taking adjuvant endocrine therapy as a treatment for breast cancer and how their beliefs about the purpose of the medication, side effects experienced and interactions with health professionals might influence adherence. Design Qualitative study using semistructured, one-to-one interviews. Setting 2 hospitals from a single health board in Scotland. Participants 30 women who had been prescribed tamoxifen or aromatase inhibitors (anastrozole or letrozole) and had been taking this medication for 1–5 years. Results Women clearly wished to take their adjuvant endocrine therapy medication as prescribed, believing that it offered them protection against breast cancer recurrence. However, some women missed tablets and did not recognise that this could reduce the efficacy of the treatment. Women did not perceive that healthcare professionals were routinely or systematically monitoring their adherence. Side effects were common and impacted greatly on the women’s quality of life but did not always cause women to stop taking their medication, or to seek advice about reducing the side effects they experienced. Few were offered the opportunity to discuss the impact of side effects or the potential options available. Conclusions Although most women in this study took adjuvant endocrine therapy as prescribed, many endured a range of side effects, often without seeking help. Advice, support and monitoring for adherence are not routinely offered in conventional follow-up settings. Women deserve more opportunity to discuss the pros, cons and impact of long-term adjuvant endocrine therapy. New service models are needed to support adherence, enhance quality of life and ultimately improve survival. These should ideally be community based, in order to promote self-management in the longer term. PMID:24928595

  4. Adjuvants are Key Factors for the Development of Future Vaccines: Lessons from the Finlay Adjuvant Platform

    PubMed Central

    Pérez, Oliver; Romeu, Belkis; Cabrera, Osmir; González, Elizabeth; Batista-Duharte, Alexander; Labrada, Alexis; Pérez, Rocmira; Reyes, Laura M.; Ramírez, Wendy; Sifontes, Sergio; Fernández, Nelson; Lastre, Miriam

    2013-01-01

    The development of effective vaccines against neglected diseases, especially those associated with poverty and social deprivation, is urgently needed. Modern vaccine technologies and a better understanding of the immune response have provided scientists with the tools for rational and safer design of subunit vaccines. Often, however, subunit vaccines do not elicit strong immune responses, highlighting the need to incorporate better adjuvants; this step therefore becomes a key factor for vaccine development. In this review we outline some key features of modern vaccinology that are linked with the development of better adjuvants. In line with the increased desire to obtain novel adjuvants for future vaccines, the Finlay Adjuvant Platform offers a novel approach for the development of new and effective adjuvants. The Finlay Adjuvants (AFs), AFPL (proteoliposome), and AFCo (cochleate), were initially designed for parenteral and mucosal applications, and constitute potent adjuvants for the induction of Th1 responses against several antigens. This review summarizes the status of the Finlay technology in producing promising adjuvants for unsolved-vaccine diseases including mucosal approaches and therapeutic vaccines. Ideas related to adjuvant classification, adjuvant selection, and their possible influence on innate recognition via multiple toll-like receptors are also discussed. PMID:24348475

  5. Non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer: a Cochrane systematic review.

    PubMed

    Kunath, Frank; Grobe, Henrik R; Rücker, Gerta; Motschall, Edith; Antes, Gerd; Dahm, Philipp; Wullich, Bernd; Meerpohl, Joerg J

    2015-07-01

    To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for treating advanced hormone-sensitive stages of prostate cancer. We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers. We included randomized controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced hormone-sensitive stages of prostate cancer. Two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, extracted data and assessed risk of bias as well as quality of evidence according to the GRADE working group guidelines. We used Review Manager 5.2 for data synthesis and the fixed-effect model as primary analysis (when heterogeneity was low with I(2) < 50%); we used a random-effects model when confronted with substantial or considerable heterogeneity (when I(2) ≥50%). A total of 11 studies involving 3060 randomly assigned participants were included in the present review. Use of non-steroidal antiandrogens resulted in lower overall survival times (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.05-1.48, six studies, 2712 participants) and greater clinical progression (1 year: risk ratio [RR] 1.25, 95% CI 1.08-1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08-1.45, six studies, 2373 participants; 2 years: RR 1.14, 95% CI 1.04-1.25, three studies, 1336 participants), as well as treatment failure (1 year: RR 1.19, 95% CI 1.02-1.38, four studies, 1539 participants; 70 weeks: RR 1

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

    PubMed Central

    Metzger Filho, Otto; Giobbie-Hurder, Anita; Mallon, Elizabeth; Gusterson, Barry; Viale, Giuseppe; Winer, Eric P.; Thürlimann, Beat; Gelber, Richard D.; Colleoni, Marco; Ejlertsen, Bent; Debled, Marc; Price, Karen N.; Regan, Meredith M.; Coates, Alan S.; Goldhirsch, Aron

    2015-01-01

    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 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 by Ki-67 labeling index. Survival analyses were performed with weighted Cox models that used inverse probability of censoring weighted modeling. Results The median follow-up time was 8.1 years. In multivariable models for disease-free survival (DFS), significant interactions between treatment and histology (ILC or IDC; P = .006) and treatment and subgroup (LB like or LA like; P = .01) were observed. In the ILC subset, there was a 66% reduction in the hazard of a DFS event with letrozole for LB (hazard ratio [HR], 0.34; 95% CI, 0.21 to 0.55) and a 50% reduction for LA subtypes (HR, 0.50; 95% CI, 0.32 to 0.78). In the IDC subset, there was a significant 35% reduction in the hazard of a DFS event with letrozole for the LB subtype (HR, 0.65; 95% CI, 0.53 to 0.79), but no difference between treatments was noted for IDC and the LA subtype (HR, 0.95; 95% CI, 0.76 to 1.20). Conclusion The magnitude of benefit of adjuvant letrozole is greater for patients diagnosed with lobular carcinoma versus ductal carcinoma. PMID:26215945

  7. Activation of the dorsal hippocampal nicotinic acetylcholine receptors improves tamoxifen-induced memory retrieval impairment in adult female rats.

    PubMed

    Tajik, Azam; Rezayof, Ameneh; Ghasemzadeh, Zahra; Sardari, Maryam

    2016-07-01

    Tamoxifen (TAM), a selective estrogen receptor modulator, has frequently been used in the treatment of breast cancer. In view of the fact that cognitive deficits in women who receive adjuvant chemotherapy for breast cancer is a common health problem, using female animal models for investigating the cognitive effects of TAM administration may improve our knowledge of TAM therapy. Therefore, the present study assessed the role of dorsal hippocampal cholinergic nicotinic receptors (nAChRs) in the effect of TAM administration on memory retrieval in ovariectomized (OVX) and non-OVX female rats using a passive avoidance learning task. Our results showed that pre-test administration of TAM (2-6mg/kg) impaired memory retrieval. Pre-test intra-CA1 microinjection of nicotine (0.3-0.5μg/rat) reversed TAM-induced memory impairment. Pre-test intra-CA1 microinjection of mecamylamine (0.1-0.3μg/rat) plus 2mg/kg (an ineffective dose) of TAM impaired memory retrieval. Pre-test intra-CA1 microinjection of the same doses of nicotine and mecamylamine by themselves had no effect on memory retrieval. In OVX rats, the administration of TAM (6mg/kg) produced memory impairment but pre-test intra-CA1 microinjection of nicotine (0.5μg/rat) had no effect on TAM response. Moreover, the administration of an ineffective dose of TAM (2mg/kg) had no effect on memory retrieval in OVX rats, while pre-test intra-CA1 microinjection of mecamylamine (0.3μg/rat) impaired memory retrieval. Taken together, it can be concluded that the impairing effect of TAM on memory formation may be modulated by nAChRs of the CA1 regions. It seems that memory impairment may be considered as an important side effect of TAM. PMID:27072849

  8. Identification of a Putative Protein Profile Associated with Tamoxifen Therapy Resistance in Breast Cancer*S⃞

    PubMed Central

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

    2009-01-01

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

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

    SciTech Connect

    Moreira, Paula I.; Custodio, Jose B.A.; Nunes, Elsa; Moreno, Antonio; Seica, Raquel; Oliveira, Catarina R.; Santos, Maria S. . E-mail: mssantos@ci.uc.pt

    2007-05-15

    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 17{beta}-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{sup 2+} delaying the opening of the permeability transition pore. The presence of 25 {mu}M 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{sub 2}O{sub 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.

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

    PubMed

    Colón, Jennifer M; Miranda, Jorge D

    2016-08-01

    Spinal cord injury (SCI) is a condition without a cure, affecting sensory and/or motor functions. The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration. Among these complex set of events are damage of the blood-brain barrier, edema formation, inflammation, oxidative stress, demyelination, reactive gliosis and apoptosis. The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival, regeneration, vascular reorganization and synaptic formation. Tamoxifen, a selective estrogen receptor modulator, is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition. Various investigators using different animal models and injury parameters have demonstrated the beneficial effects of this drug to improve functional locomotor recovery after SCI. Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant, anti-inflammatory and anti-gliotic responses. A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment. In addition, the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated. This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the field. PMID:27651756

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2012-01-01

    Therapies that target estrogen signaling have made a very considerable contribution to reducing mortality from breast cancer. However, resistance to tamoxifen remains a major clinical problem. Here we have used a genome-wide functional profiling approach to identify multiple genes that confer resistance or sensitivity to tamoxifen. Combining whole-genome shRNA screening with massively parallel sequencing, we have profiled the impact of more than 56,670 RNA interference reagents targeting 16,487 genes on the cellular response to tamoxifen. This screen, along with subsequent validation experiments, identifies a compendium of genes whose silencing causes tamoxifen resistance (including BAP1, CLPP, GPRC5D, NAE1, NF1, NIPBL, NSD1, RAD21, RARG, SMC3, and UBA3) and also a set of genes whose silencing causes sensitivity to this endocrine agent (C10orf72, C15orf55/NUT, EDF1, ING5, KRAS, NOC3L, PPP1R15B, RRAS2, TMPRSS2, and TPM4). Multiple individual genes, including NF1, a regulator of RAS signaling, also correlate with clinical outcome after tamoxifen treatment. PMID:21482774

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

    PubMed Central

    Colón, Jennifer M.; Miranda, Jorge D.

    2016-01-01

    Spinal cord injury (SCI) is a condition without a cure, affecting sensory and/or motor functions. The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration. Among these complex set of events are damage of the blood-brain barrier, edema formation, 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. PMID:27651756

  14. Interaction of the anticancer drug tamoxifen with the human erythrocyte membrane and molecular models.

    PubMed

    Suwalsky, M; Hernández, P; Villena, F; Aguilar, F; Sotomayor, C P

    1998-01-01

    Tamoxifen is a non steroidal antiestrogen drug extensively used in the prevention and treatment of hormone-dependent breast cancer. To evaluate its perturbing effect upon cell membranes it was made to interact with human erythrocytes and molecular models. These consisted of bilayers of dimyristoylphosphatidylcholine (DMPC) and of dimyristoylphosphatidylethanolamine (DMPE), representative of phospholipids classes located in the outer and inner leaflets of the erythrocyte membrane, respectively. Experiments by fluorescence spectroscopy showed that tamoxifen interacted with DMPC vesicles fluidizing both its polar head and acyl chain regions. These results were confirmed by X-ray diffraction which indicated that tamoxifen perturbed the same regions of the lipid. However, it did not cause any significant structural perturbation to DMPE bilayers. The examination by electron microscopy of human erythrocytes incubated with tamoxifen revealed that they changed their normal discoid shape to stomatocytes. According to the bilayer couple hypothesis, this result means that the drug is inserted in the inner leaflet of the erythrocyte membrane. Given the fact that tamoxifen did not interact with DMPE, it is concluded that it interacted with a protein located in the cytoplasmic moiety of the erythrocyte membrane. PMID:9618934

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

    PubMed Central

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

    2016-01-01

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

  16. Alteration of rat hippocampal neurogenesis and neuronal nitric oxide synthase expression upon prenatal exposure to tamoxifen.

    PubMed

    Nobakht, Maliheh; Gharavi, Mohammad Javad; Mousavizadeh, Kazem; Bakhshayesh, Maasoumeh; Ghafourifar, Pedram

    2011-09-01

    The present study delineates the effect of tamoxifen on neuronal density and expression of neuronal nitric oxide synthase (nNOS) in hippocampal nerve cells during prenatal and postnatal periods in rats. Pregnant rats were administered with tamoxifen one day prior to labor (E21) and on the childbirth day (E22). Hippocampi of embryos at E22 and newborns at postnatal days of 1, 7, and 21 (P1, P7, and P21) were investigated. Density of the neurons in areas of the developing hippocampus including cornu ammonis (CA1, CA3), dentate gyrus, and subiculum were studied. Our findings show that the number of pyramidal neurons was significantly decreased in CA1 and subiculum of tamoxifen-treated rats in E22, P1, and P7. We found that cellular density was lower in early stages of development, however, cellular density and thickness gradually increased during the development particularly in the third week. We found that nNOS expression was decreased in E22, P1, and P7 in animals treated with tamoxifen. The present study shows that tamoxifen affects development and differentiation of postnatal rat hippocampus, CA1 neurons, and nNOS expression.

  17. Tamoxifen Metabolite Concentrations, CYP2D6 Genotype and Breast Cancer Outcomes

    PubMed Central

    Madlensky, Lisa; Natarajan, Loki; Tchu, Simone; Pu, Minya; Mortimer, Joanne; Flatt, Shirley W.; Nikoloff, D. Michele; Hillman, Grantland; Fontecha, Marcel R.; Lawrence, H. Jeffrey; Parker, Barbara A.; Wu, Alan H.B.; Pierce, John P.

    2011-01-01

    We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen, and to examine potential correlates of endoxifen concentrations including CYP2D6 metabolizer phenotype and body mass index (BMI). Tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen concentrations were measured from 1370 estrogen receptor positive breast cancer patients participating in the Women’s Healthy Eating and Living (WHEL) Study, and tested for associations with breast cancer outcomes. Breast cancer outcomes were not associated with tamoxifen, 4-hydroxytamoxifen or N-desmethyltamoxifen concentrations. For endoxifen, a threshold was identified suggesting that women in the upper four quintiles of endoxifen had a 26% lower recurrence rate than women in the bottom quintile. (HR=0.74; 95% CI, [0.55, 1.00]). Predictors of membership in this higher risk bottom quintile were poor/intermediate metabolizer genotype, higher BMI, and low tamoxifen concentrations. This study suggests a minimal threshold at which endoxifen is effective against breast cancer recurrence, which 80% of tamoxifen-takers achieve. PMID:21430657

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

    PubMed

    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.

  19. Resveratrol sensitizes tamoxifen in antiestrogen-resistant breast cancer cells with epithelial-mesenchymal transition features.

    PubMed

    Shi, Xiao-Peng; Miao, Shan; Wu, Yin; Zhang, Wei; Zhang, Xiao-Fang; Ma, Hua-Zhao; Xin, Hai-Li; Feng, Juan; Wen, Ai-Dong; Li, Yan

    2013-07-26

    Tamoxifen resistance remains to be a huge obstacle in the treatment of hormone-dependent breast cancer, and this therefore highlights the dire need to explore the underlying mechanisms. The epithelial-mesenchymal transition (EMT) is a molecular process through which an epithelial cell transfers into a mesenchymal phenotype. Roles of EMT in embryo development, cancer invasion and metastasis have been extensively reported. Herein, we established tamoxifen-resistant MCF-7/TR breast cancer cells and showed that MCF-7/TR cells underwent EMT driven by enhanced endogenous TGF-β/Smad signaling. Ectopic supplement of TGF-β promoted in MCF-7 cells a mesenchymal and resistant phenotype. In parallel, we demonstrated that resveratrol was capable of synergizing with tamoxifen and triggering apoptosis in MCF-7/TR cells. Further Western blot analysis indicated that the chemosensitizing effects of resveratrol were conferred with its modulation on endogenous TGF-β production and Smad phosphorylation. In particular, 50 μM resveratrol had minor effects on MCF-7/TR cell proliferation, but could significantly attenuate endogenous TGF-β production and the Smad pathway, ultimately leading to reversion of EMT. Collectively, our study highlighted distinct roles of EMT in tamoxifen resistance and resveratrol as a potential agent to overcome acquired tamoxifen resistance. The molecular mechanism of resveratrol chemosensitizing effects is, at least in part, TGF-β/Smad-dependent.

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

    PubMed Central

    Nery-Aguiar, Afif Rieth; Aguiar, Yousef Qathaf; Júnior, Airton Mendes Conde; Alencar, Airlane Pereira; Tavares, Cleciton Braga; Lopes-Costa, Pedro Vitor; Nazário, Afonso Celso; da Silva, Benedito Borges

    2016-01-01

    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. PMID:26934238

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

    PubMed Central

    Colón, Jennifer M.; Miranda, Jorge D.

    2016-01-01

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

  2. Immunological adjuvants: a role for liposomes.

    PubMed

    Gregoriadis, G

    1990-03-01

    Recent technological advances have resulted in the production of safe subunit and synthetic small peptide vaccines. These vaccines are weakly or non-immunogenic and cannot, therefore, be used effectively in the absence of immunological adjuvants (agents that can induce strong immunity to antigens). Owing to the toxicity of adjuvants, only one (aluminium salts) has hitherto been licensed for use in humans, and it is far from ideal. In this article, Gregory Gregoriadis discusses the use of liposomes as an alternative safe, versatile, universal adjuvant that can induce humoral- and cell-mediated immunity to antigens when administered parenterally or enterally. PMID:2186746

  3. Pharmacotherapy of acute mania: monotherapy or combination therapy with mood stabilizers and antipsychotics?

    PubMed

    Grande, Iria; Vieta, Eduard

    2015-03-01

    The use of combination therapy with mood stabilizers and antipsychotics in acute mania in bipolar disorder (BD) is widespread, although most treatment guidelines recommend monotherapy as the first option, and reserve combination therapy, which is associated with more frequent and more severe side effects, for when patients do not respond to the former treatment option. Reasons to prescribe combination therapy include the lack of efficacy of the current treatment (either real or due to undisclosed poor adherence), psychiatric comorbidities, severe previous course of illness, slow cross-tapering during treatment switching, and potential benefits from particular combinations. The decision to start with monotherapy or combination therapy may depend on the patient characteristics, and is still under debate. Clinical trials designed to ascertain whether combination therapy or monotherapy is more advantageous for patients in acute mania and beyond, according to illness severity, are urgently needed. Adding a third monotherapy arm to the conventional two-arm, adjunctive-design trials or initiating combination therapy from the beginning may help to shed some light on the issue.

  4. Efficacy of monotherapies and artesunate-based combination therapies in children with uncomplicated malaria in Somalia.

    PubMed

    Warsame, Marian; Atta, Hoda; Klena, John D; Waqar, Butt Ahmed; Elmi, Hussein Haji; Jibril, Ali Mohamed; Hassan, Hassan Mohamed; Hassan, Abdullahi Mohamed

    2009-02-01

    In order to guide the antimalarial treatment policy of Somalia, we conducted therapeutic efficacy studies of routinely used antimalarial monotherapies as well as artemisinin-based combination therapies (ACTs) for uncomplicated malaria in three sentinel sites during 2003-2006. Therapeutic efficacy of chloroquine (CQ), amodiaquine (AQ) and sulfadoxine/pyrimetahmine (SP) monotherapies, and artesunate plus SP (AS+SP) or AQ (AS+AQ) were evaluated in children 6 months to 10 years old with uncomplicated malaria. For the assessment of the monotherapies, 2003 WHO protocol with 14-day follow-up was used while the 2005 WHO protocol with 28-day follow-up was used for testing the ACTs. Of the monotherapies, CQ performed very poorly with treatment failures varying from 76.5% to 88% between the sites. AQ treatment failure was low except for Janale site with treatment failure of 23.4% compared to 2.8% and 8% in Jamame and Jowhar, respectively. For SP, treatment failures from 7.8% to 12.2% were observed. A 28-day test of artemisinin-based combinations, AS+SP and AS+AQ, proved to be highly efficacious with cure rates of 98-100% supporting the choice of AS+SP combination as first line treatment for uncomplicated malaria for Somalia.

  5. 17beta-estradiol and tamoxifen stimulate rapid and transient ERK activationin MCF-7 cells via distinct signaling mechanisms.

    PubMed

    Visram, Hasina; Greer, Peter A

    2006-12-01

    Traditionally, estrogen signaling was thought to be mediated strictly through genomic pathways. Recently, however, it has been demonstrated that estrogen stimulation of cells leads to rapid nongenomic effects including ERK activation. While the precise mechanism of this action is still under investigation, it is known that activation of the epidermal growth factor receptor, the Src tyrosine kinase, and metalloproteinases are involved in this process. More recently, tamoxifen, an anti-hormonal agent used to treat breast cancer, has been shown to also activate ERK. The pathways by which it does so, however, are not known. Using the MCF-7 human breast carcinoma cell line as a model system, we show that ERK is rapidly and transiently activated in cells challenged with epidermal growth factor (EGF), 17beta-estradiol (E2) or tamoxifen. The ERK activation response to E2 and tamoxifen was kinetically similar, although the response to tamoxifen was delayed relative to that of E2 stimulation. The effect of the EGFR inhibitor AG1517 revealed that E2 and tamoxifen were both equally dependent on EGFR for activation of ERK. In contrast, inhibition of Src or metalloproteinases caused distinct effects on ERK activation by E2 and tamoxifen. Thus, while both E2 and tamoxifen induced activation of ERK, the differences in the effects of inhibitors of Src or metalloproteinases on ERK activation indicated that E2 and tamoxifen do so via distinct molecular mechanisms.

  6. NGX6 expression improves the sensitivity of tamoxifen-resistant MCF-7 cells through modulation of the Smad signaling pathway.

    PubMed

    Zhao, Wen-Jing; Wang, Ke

    2013-06-01

    The effects of nasopharyngeal carcinoma-associated gene 6 (NGX6) in breast cancer was studied. We demonstrated that the levels of the NGX6 protein and mRNA were lower in patients with tamoxifen-resistant tumors compared to patients with tamoxifen-sensitive tumors. Tamoxifen was able to decrease proliferation, increase apoptosis and induce G1 arrest in NGX6-expressing TRM-7 cells in vitro. In order to detect the mechanism(s) of tamoxifen action, we first obtain the three-dimensional structure of the NGX6 protein by using Protein Homology/analogY Recognition Engine (PHYRE). Prediction of the docking between the NGX6 protein and tamoxifen was performed using SYBYL-X 1.3. Furthermore, we found that tamoxifen activated Smad2/3, and increased the expression of Smad4 in NGX6-expressing TRM-7 cells as evaluated by western blot analysis. Smad2/3-targeted siRNA was used to confirm the mechanism(s) of tamoxifen action in NGX6-expressing cells. These results indicated that NGX6 may increase the sensitivity of breast cancer cells to tamoxifen.

  7. Effects of In Vivo Exposure to Tamoxifen on a Non-Target Species, the Marine Fish Cunner (Tautogolabrus adspersus)

    EPA Science Inventory

    Tamoxifen is an endocrine-active pharmaceutical that is used world-wide to treat certain breast cancers. Because tamoxifen has been detected in aquatic environments, a study was undertaken to investigate its biological effects in a non-target species, the marine fish cunner (Taut...

  8. Chemotherapy-Related Amenorrhea after Adjuvant Paclitaxel-Trastuzumab (APT Trial)

    PubMed Central

    Ruddy, Kathryn J.; Guo, Hao; Barry, William; Dang, Chau T.; Yardley, Denise A.; Moy, Beverly; Marcom, P. Kelly; Albain, Kathy S.; Rugo, Hope S.; Ellis, Matthew J.; Shapira, Iuliana; Wolff, Antonio C.; Carey, Lisa A.; Overmoyer, Beth A.; Hudis, Clifford; Krop, Ian E.; Burstein, Harold J.; Winer, Eric P.; Partridge, Ann H.; Tolaney, Sara M.

    2016-01-01

    Purpose Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50% of all premenopausal recipients [1]. Methods 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3cm node-negative HER2+ breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Results Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28%, 95% CI 18-41%) were amenorrheic at that time point. Conclusions Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms. PMID:25981899

  9. Self nanoprecipitating preconcentrate of tamoxifen citrate for enhanced bioavailability.

    PubMed

    Kapse, Sonali V; Gaikwad, Rajiv V; Samad, Abdul; Devarajan, Padma V

    2012-06-15

    We disclose a self nanoprecipitating preconcentrate (SNP) of tamoxifen citrate (TMX), which forms TMX loaded polymeric nanoparticles, on dilution with aqueous media. SNP comprised TMX, polymer (Kollidon SR) and surfactant/s dissolved in a pharmaceutically acceptable vehicle. Binary surfactant mixtures of Aerosol OT (AOT) with Tween 80 revealed synergistic reduction in surface tension to enable both high entrapment efficiency (EE) and low particle size (PS). Synergism of the surfactants was confirmed by molecular interaction parameter(β(σ)). Combination of AOT and Tween 80 resulted in EE (∼85%) and PS (<250nm). Formation of TMX-KSR nanoparticles in situ was reproducible under most experimental conditions and exhibited pH independent behavior. Dilution volume (>80mL) influenced both PS and EE while dilution temperature influenced only PS. Marginal increase in size was evident at the end of 1h nevertheless was not of concern as TMX SNP exhibited near complete release in 1h. DSC and XRD studies revealed amorphous nature of TMX in nanoparticles. FTIR imaging confirmed uniform distribution of TMX in nanoparticles. ESEM and TEM revealed spherical nanoparticles. Biodistribution studies of (99m)Tc labeled TMX SNP in rats revealed no significant absorption however oral pharmacokinetics revealed enhanced oral bioavailability of TMX (165%) compared to TMX suspension. SNP presents a new in situ approach, for design of drug loaded polymeric nanoparticles. PMID:22414426

  10. Memory enhancement by Tamoxifen on amyloidosis mouse model.

    PubMed

    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.

  11. Tamoxifen reduces fat mass by boosting reactive oxygen species.

    PubMed

    Liu, L; Zou, P; Zheng, L; Linarelli, L E; Amarell, S; Passaro, A; Liu, D; Cheng, Z

    2015-01-01

    As the pandemic of obesity is growing, a variety of animal models have been generated to study the mechanisms underlying the increased adiposity and development of metabolic disorders. Tamoxifen (Tam) is widely used to activate Cre recombinase that spatiotemporally controls target gene expression and regulates adiposity in laboratory animals. However, a critical question remains as to whether Tam itself affects adiposity and possibly confounds the functional study of target genes in adipose tissue. Here we administered Tam to Cre-absent forkhead box O1 (FoxO1) floxed mice (f-FoxO1) and insulin receptor substrate Irs1/Irs2 double floxed mice (df-Irs) and found that Tam induced approximately 30% reduction (P<0.05) in fat mass with insignificant change in body weight. Mechanistically, Tam promoted reactive oxygen species (ROS) production, apoptosis and autophagy, which was associated with downregulation of adipogenic regulator peroxisome proliferator-activated receptor gamma and dedifferentiation of mature adipocytes. However, normalization of ROS potently suppressed Tam-induced apoptosis, autophagy and adipocyte dedifferentiation, suggesting that ROS may account, at least in part, for the changes. Importantly, Tam-induced ROS production and fat mass reduction lasted for 4-5 weeks in the f-FoxO1 and df-Irs mice. Our data suggest that Tam reduces fat mass via boosting ROS, thus making a recovery period crucial for posttreatment study. PMID:25569103

  12. Tamoxifen promotes differentiation of oligodendrocyte progenitors in vitro.

    PubMed

    Barratt, H E; Budnick, H C; Parra, R; Lolley, R J; Perry, C N; Nesic, O

    2016-04-01

    The most promising therapeutic approach to finding the cure for devastating demyelinating conditions is the identification of clinically safe pharmacological agents that can promote differentiation of endogenous oligodendrocyte precursor cells (OPCs). Here we show that the breast cancer medication tamoxifen (TMX), with well-documented clinical safety and confirmed beneficial effects in various models of demyelinating conditions, stimulates differentiation of rat glial progenitors to mature oligodendrocytes in vitro. Clinically applicable doses of TMX significantly increased both the number of CNPase-positive oligodendrocytes and protein levels of myelin basic protein, measured with Western blots. Furthermore, we also found that OPC differentiation was stimulated, not only by the pro-drug TMX-citrate (TMXC), but also by two main TMX metabolites, 4-hydroxy-TMX and endoxifen. Differentiating effects of TMXC and its metabolites were completely abolished in the presence of estrogen receptor (ER) antagonist, ICI182780. In contrast to TMXC and 4-hydroxy-TMX, endoxifen also induced astrogliogenesis, but independent of the ER activation. In sum, we showed that the TMX prodrug and its two main metabolites (4-hydroxy-TMX and endoxifen) promote ER-dependent oligodendrogenesis in vitro, not reported before. Given that differentiating effects of TMX were achieved with clinically safe doses, TMX is likely one of the most promising FDA-approved drugs for the possible treatment of demyelinating diseases. PMID:26820594

  13. Interactions of the Anticancer Drug Tamoxifen with Lipid Membranes

    PubMed Central

    Khadka, Nawal K.; Cheng, Xiaolin; Ho, Chian Sing; Katsaras, John; Pan, Jianjun

    2015-01-01

    Interactions of the hydrophobic anticancer drug tamoxifen (TAM) with lipid model membranes were studied using calcein-encapsulated vesicle leakage, attenuated total reflection Fourier transform infrared (FTIR) spectroscopy, small-angle neutron scattering (SANS), atomic force microscopy (AFM) based force spectroscopy, and all-atom molecular dynamics (MD) simulations. The addition of TAM enhances membrane permeability, inducing calcein to translocate from the interior to the exterior of lipid vesicles. A large decrease in the FTIR absorption band’s magnitude was observed in the hydrocarbon chain region, suggesting suppressed bond vibrational dynamics. Bilayer thickening was determined from SANS data. Force spectroscopy measurements indicate that the lipid bilayer area compressibility modulus KA is increased by a large amount after the incorporation of TAM. MD simulations show that TAM decreases the lipid area and increases chain order parameters. Moreover, orientational and positional analyses show that TAM exhibits a highly dynamic conformation within the lipid bilayer. Our detailed experimental and computational studies of TAM interacting with model lipid membranes shed new light on membrane modulation by TAM. PMID:25992727

  14. Memory enhancement by Tamoxifen on amyloidosis mouse model.

    PubMed

    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. PMID:26435474

  15. Novel Adjuvants and Immunomodulators for Veterinary Vaccines.

    PubMed

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

    2016-01-01

    Adjuvants are crucial for efficacy of vaccines, especially subunit and recombinant vaccines. Rational vaccine design, including knowledge-based and molecularly defined adjuvants tailored for directing and potentiating specific types of host immune responses towards the antigens included in the vaccine is becoming a reality with our increased understanding of innate and adaptive immune activation. This will allow future vaccines to induce immune reactivity having adequate specificity as well as protective and recallable immune effector mechanisms in appropriate body compartments, including mucosal surfaces. Here we describe these new developments and, when possible, relate new immunological knowledge to the many years of experience with traditional, empirical adjuvants. Finally, some protocols are given for production of emulsion (oil-based) and liposome-based adjuvant/antigen formulations.

  16. Extended Adjuvant Therapy for Breast Cancer

    Cancer.gov

    An NCI Cancer Currents blog on findings from a recent clinical trial which showed that extending adjuvant therapy with an aromatase inhibitor can have important benefits for some women with early-stage cancer.

  17. Adjuvant Bisphosphonates for Postmenopausal Breast Cancer

    Cancer.gov

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

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

    PubMed

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

    2013-08-01

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

  19. A study of endometrial adenocarcinoma treated with tamoxifen by scanning and transmission electron microscopy.

    PubMed

    Rigano, A; Irato, S; Scalisi, R; Adamo, V; Altavilla, G; Buda, C

    1985-01-01

    By scanning and transmission electron microscopy the Authors studied four cases of endometrial adenocarcinoma (stage I, G1) after 15-days treatment with Tamoxifen (20 mg X 2) before surgery. The ultrastructural findings, similar to those observed in untreated adenocarcinomas but quite different from those obtained in MAP-responsive cases - as other Authors reported too - seem to indicate an almost complete absence of secretory or cytotoxic induction at least as far as 15-days treatment is concerned. According to the Authors this study raises many doubts about the usefulness of a first-instance therapeutical protocol based on Tamoxifen alone. However they believe that Tamoxifen can be utilized combined with a progestational agent in a simultaneous or sequence treatment.

  20. Tamoxifen does not inhibit the swell activated chloride channel in human neutrophils during the respiratory burst

    SciTech Connect

    Ahluwalia, Jatinder

    2008-10-31

    Effective functioning of neutrophils relies upon electron translocation through the NADPH oxidase (NOX). The electron current generated (I{sub e}) by the neutrophil NADPH oxidase is electrogenic and rapidly depolarises the membrane potential in activated human neutrophils. Swelling activated chloride channels have been demonstrated in part to counteract the depolarisation generated by the NADPH oxidase I{sub e}. In the present study, the effects of inhibitors of swell activated chloride channels on ROS production and on the swelling activated chloride conductance was investigated in activated human neutrophils. Tamoxifen (10 {mu}M), a specific inhibitor for swell activated chloride channels in neutrophils, completely inhibited both the PMA and FMLP stimulated respiratory burst. This inhibition of the neutrophil respiratory burst was not due to the blocking effect of tamoxifen on the swelling activated chloride conductance in these cells. These results demonstrate that a tamoxifen insensitive swell activated chloride channel has important significance during the neutrophil respiratory burst.

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

    PubMed

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

    2013-08-01

    Long term tamoxifen citrate therapy is imperative to treat several dermatological and hormonal sensitive disorders. Successful oral and parenteral administration of tamoxifen citrate has been challenging since it undergoes enzymatic degradation and has poor aqueous solubility issues. In the present work, tamoxifen citrate loaded ethosomes were prepared and characterized for transdermal applications. The prepared formulations were characterized for morphological features, particle size distribution, calorimetric attributes, zeta potential and drug entrapment. Permeation profile of prepared ethosomes was compared with liposomes and hydroethonalic solution across cellophane membrane and human cadaver skin. Results of the permeation studies indicate that ethosomes were able to deliver >90% drug within 24 hours of application, while liposomes and hydroethanolic solution delivered only 39.04% and 36.55% respectively. Skin deposition and stability studies are also reported. PMID:23656399

  2. Tamoxifen metabolite endoxifen interferes with the polyamine pathway in breast cancer.

    PubMed

    Thomas, T J; Thomas, Thresia; John, Shali; Hsu, Hui-Chen; Yang, PingAr; Keinänen, Tuomo A; Hyvönen, Mervi T

    2016-10-01

    Tamoxifen is the most widely used drug to treat women with estrogen receptor α (ERα)-positive breast cancer. Endoxifen is recognized as the active metabolite of tamoxifen in humans. We studied endoxifen effects on ERα-positive MCF-7 breast cancer cells. Estradiol increased the proliferation of MCF-7 cells by two- to threefold and endoxifen suppressed its effects. Endoxifen suppressed c-myc, c-fos and Tff1 oncogene expression, as revealed by RT-PCR. Estradiol increased the activity of ornithine decarboxylase (ODC) and adenosyl methioninedecarboxylase (AdoMetDC), whereas endoxifen suppressed these enzyme activities. Endoxifen increased activities of spermine oxidase (SMO) and acetyl polyamine oxidase (APAO) significantly, and reduced the levels of putrescine and spermidine. These data suggest a possible mechanism for the antiestrogenic effects of tamoxifen/endoxifen, involving the stimulation of polyamine oxidase enzymes. Therefore, SMO and APAO stimulation might be useful biomarkers for the efficacy of endoxifen treatment of breast cancer.

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

    PubMed

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

    2013-01-01

    The tropical edible red seaweed (Eucheuma cottonii L.) is rich in nutrients and polyphenolic compounds that may suppress cancer through its antioxidant and antiproliferative properties. The study reports on rat mammary tumor suppression and tissue antioxidant status modulation by E. cottonii ethanol extract (ECE). The effect of orally administered ECE (100 mg/kg body-weight) was compared with that of tamoxifen (10 mg/kg body-weight). Rat was induced to develop mammary tumor with subcutaneous injection of LA-7 cells (6 × 10(6) cells/rat). The ECE was more effective than tamoxifen in suppressing tumor growth (27%), improving tissues (plasma, liver, and kidney) malondialdehyde concentrations, superoxide dismutase activity and erythrocyte glutathione concentrations (P < 0.05). Unlike tamoxifen, the ECE displayed little toxicity to the liver and kidneys. The ECE exhibited strong anticancer effect with enzyme modulating properties, suggesting its potential as a suppressing agent for mammary gland tumor. PMID:23441613

  4. Calcium channel antagonist properties of the antineoplastic antiestrogen tamoxifen in the PC12 neurosecretory cell line

    SciTech Connect

    Greenberg, D.A.; Carpenter, C.L.; Messing, R.O.

    1987-01-01

    In view of existing evidence that Ca2+ may be important for tumor cell growth and metastasis, we investigated the effects of three antineoplastic drugs on K+-stimulated /sup 45/Ca2+ uptake through voltage-dependent Ca2+ channels of the PC12 neurosecretory cell line. The agents chosen for study (vinblastine, doxorubicin, and tamoxifen) were those previously shown to inhibit Ca2+/calmodulin- or Ca2+/phospholipid-activated protein kinases. Neither vinblastine nor doxorubicin altered /sup 45/Ca2+ uptake at concentrations that inhibit these Ca2+-dependent enzymes. However, tamoxifen reduced uptake (50% inhibitory dose, 8.6 +/- 0.9 (SE) microM) and competed for Ca2+ channel antagonist binding sites labeled by (/sup 3/H)-(+)PN200-110 (ki = 2.2 +/- 0.3 microM). Ca2+ channel antagonist properties may contribute to the effects of antineoplastic agents such as tamoxifen.

  5. Benefit/Risk Assessment for Breast Cancer Chemoprevention With Raloxifene or Tamoxifen for Women Age 50 Years or Older

    PubMed Central

    Freedman, Andrew N.; Yu, Binbing; Gail, Mitchell H.; Costantino, Joseph P.; Graubard, Barry I.; Vogel, Victor G.; Anderson, Garnet L.; McCaskill-Stevens, Worta

    2011-01-01

    Purpose The Study of Tamoxifen and Raloxifene (STAR) demonstrated that raloxifene was as effective as tamoxifen in reducing the risk of invasive breast cancer (IBC) in postmenopausal women and had lower risks of thromboembolic events, endometrial cancer, and cataracts but had a nonstatistically significant higher risk of noninvasive breast cancer. There is a need to summarize the risks and benefits of these agents. Patients and Methods Baseline incidence rates of IBC and other health outcomes, absent raloxifene and tamoxifen, were estimated from breast cancer chemoprevention trials; the Surveillance, Epidemiology and End Results Program; and the Women's Health Initiative. Effects of raloxifene and tamoxifen were estimated from STAR and the Breast Cancer Prevention Trial. We assigned weights to health outcomes to calculate the net benefit from raloxifene compared with placebo and tamoxifen compared with placebo. Results Risks and benefits of treatment with raloxifene or tamoxifen depend on age, race, breast cancer risk, and history of hysterectomy. Over a 5-year period, postmenopausal women with an intact uterus had a better benefit/risk index for raloxifene than for tamoxifen. For postmenopausal women without a uterus, the benefit/risk ratio was similar. The benefits and risks of raloxifene and tamoxifen are described in tables that can help identify groups of women for whom the benefits outweigh the risks. Conclusion We developed a benefit/risk index to quantify benefits from chemoprevention with tamoxifen or raloxifene. This index can complement clinical evaluation in deciding whether to initiate chemoprevention and in comparing the benefits and risks of raloxifene versus tamoxifen. PMID:21537036

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

    SciTech Connect

    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.

    2007-11-15

    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{sub 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.

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

    PubMed

    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. PMID:27400912

  8. Tamoxifen inhibits osteoclast-mediated resorption of trabecular bone in ovarian hormone-deficient rats.

    PubMed

    Turner, R T; Wakley, G K; Hannon, K S; Bell, N H

    1988-03-01

    The effects of the nonsteroidal antiestrogen tamoxifen were determined on trabecular bone mass in the proximal tibial metaphysis of intact and ovariectomized rats. Rats were ovariectomized at the beginning of the study. On day 7 of the study, 5-mg slow release pellets of tamoxifen or placebo were implanted sc. All of the rats were killed on day 28 of the experiment. Sections of the proximal tibial metaphysis were stained for acid phosphatase and evaluated histomorphometrically. Ovariectomy resulted in marked loss of bone. Compared to the values in sham-operated animals, the trabecular bone at a sampling site in the secondary spongiosa of ovariectomized rats was reduced by more than 60%, the length of trabecular bone surface covered by osteoclasts was increased by 563%, the percentage of trabecular bone surface covered by osteoclasts was increased by 567%, the mean osteoclast size was increased by 84%, and the number of nuclei per osteoclast was increased by 38%. In contrast, treatment of ovariectomized rats for 3 weeks with tamoxifen restored the histomorphometric measurements to values comparable to those in sham-operated animals. 17 beta-Estradiol increased trabecular bone fractional area in ovariectomized and sham-operated rats, and administration of tamoxifen to estrogen-treated, ovariectomized, and sham-operated animals produced a further increase in trabecular bone. In summary, 1) ovariectomy resulted in large increases in both the number and activity of osteoclasts, 2) the increased bone resorption associated with ovariectomy produced a net loss of trabecular bone, and 3) treatment of ovariectomized rats with tamoxifen prevented these skeletal changes. The results indicate that in the rat, tamoxifen mimics the effects of estrogen on trabecular bone at concentrations that are not uterotropic.

  9. Structural insights into selective agonist actions of tamoxifen on human Estrogen Receptor alpha

    PubMed Central

    Chakraborty, Sandipan; Biswas, P. K.

    2014-01-01

    Tamoxifen, an anti-estrogenic ligand in breast tissues and being used as a first-line treatment in ER-positive breast cancers, is found to develop resistance followed by resumption of growth of the tumor in about 30% of cases. Whether tamoxifen starts assisting in proliferation in such cases or there exists any ligand-independent pathways to transcription is not fully understood; also, no ERα mutants have been detected so far which could lead to tamoxifen resistance. Performing in-silico conformational analysis of ERα ligand binding domain, in the absence and presence of selective agonist (Diethylstilbestrol; DES), antagonist (Faslodex; ICI), and SERM (4-hydroxy tamoxifen; 4-OHT) ligands, we elucidated ligand-responsive structural modulations of ERα-LBD dimer in their agonist and antagonist complexes and address the issue of “tamoxifen resistance”. We found DES and ICI to stabilize the dimer in their agonist and antagonist conformations, respectively. The ERα-LBD dimer without the presence of any bound ligand also leads to a stable structure in agonist conformation. However, the binding of 4-OHT to antagonist structure is found to lead to a flexible conformation allowing the protein visiting conformations populated by agonists as are evident from principal component analysis and radius of gyration plots. Further, the relaxed conformations of the 4-OHT bound protein is found to exhibit a diminished size of the co-repressor binding pocket at LBD, thus signaling a partial blockage of the co-repressor binding motif. Thus, the ability of 4-OHT bound ERα-LBD to assume flexible conformations visited by agonists and reduced co-repressor binding surface at LBD provide crucial structural insights into tamoxifen-resistance complementing our existing understanding. PMID:25060147

  10. Novel selective estrogen mimics for the treatment of tamoxifen-resistant breast cancer.

    PubMed

    Molloy, Mary Ellen; White, Bethany E Perez; Gherezghiher, Teshome; Michalsen, Bradley T; Xiong, Rui; Patel, Hitisha; Zhao, Huiping; Maximov, Philipp Y; Jordan, V Craig; Thatcher, Gregory R J; Tonetti, Debra A

    2014-11-01

    Endocrine-resistant breast cancer is a major clinical obstacle. The use of 17β-estradiol (E2) has reemerged as a potential treatment option following exhaustive use of tamoxifen or aromatase inhibitors, although side effects have hindered its clinical usage. Protein kinase C alpha (PKCα) expression was shown to be a predictor of disease outcome for patients receiving endocrine therapy and may predict a positive response to an estrogenic treatment. Here, we have investigated the use of novel benzothiophene selective estrogen mimics (SEM) as an alternative to E2 for the treatment of tamoxifen-resistant breast cancer. Following in vitro characterization of SEMs, a panel of clinically relevant PKCα-expressing, tamoxifen-resistant models were used to investigate the antitumor effects of these compounds. SEM treatment resulted in growth inhibition and apoptosis of tamoxifen-resistant cell lines in vitro. In vivo SEM treatment induced tumor regression of tamoxifen-resistant T47D:A18/PKCα and T47D:A18-TAM1 tumor models. T47D:A18/PKCα tumor regression was accompanied by translocation of estrogen receptor (ER) α to extranuclear sites, possibly defining a mechanism through which these SEMs initiate tumor regression. SEM treatment did not stimulate growth of E2-dependent T47D:A18/neo tumors. In addition, unlike E2 or tamoxifen, treatment with SEMs did not stimulate uterine weight gain. These findings suggest the further development of SEMs as a feasible therapeutic strategy for the treatment of endocrine-resistant breast cancer without the side effects associated with E2.

  11. IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer.

    PubMed

    Sun, X; Mao, Y; Wang, J; Zu, L; Hao, M; Cheng, G; Qu, Q; Cui, D; Keller, E T; Chen, X; Shen, K; Wang, J

    2014-06-01

    Cancer-associated fibroblasts (CAFs) have been implicated in the development of resistance to anticancer drugs; however, the role and mechanism underlying CAFs in luminal breast cancer (BrCA) tamoxifen resistance are unclear. We found that stromal fibroblasts isolated from the central or peripheral area of BrCA have similar CAF phenotype and activity. In vitro and in vivo experiments showed that CAFs derived from clinical-luminal BrCAs induce tamoxifen resistance through decreasing estrogen receptor-α (ER-α) level when cultured with luminal BrCA cell lines MCF7 and T47D. CAFs promoted tamoxifen resistance through interleukin-6 (IL-6) secretion, which activates Janus kinase/signal transducers and activators of transcription (JAK/STAT3) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways in tumor cells, followed by induction of epithelial-mesenchymal transition and upregulation of E3 ubiquitin ligase anaphase-promoting complex 10 activity, which targeted ER-α degradation through the ubiquitin-proteasome pathway. Inhibition of proteasome activity, IL-6 activity or either the JAK/STAT3 or PI3K/AKT pathways markedly reduced CAF-induced tamoxifen resistance. In xenograft experiments of CAFs mixed with MCF7 cells, CAF-specific IL-6 knockdown inhibited tumorigenesis and restored tamoxifen sensitivity. These findings indicate that CAFs mediate tamoxifen resistance through IL-6-induced degradation of ER-α in luminal BrCAs.Oncogene advance online publication, 9 June 2014; doi:10.1038/onc.2014.158.

  12. Applications of nanomaterials as vaccine adjuvants

    PubMed Central

    Zhu, Motao; Wang, Rongfu; Nie, Guangjun

    2014-01-01

    Vaccine adjuvants are applied to amplify the recipient's specific immune responses against pathogen infection or malignancy. A new generation of adjuvants is being developed to meet the demands for more potent antigen-specific responses, specific types of immune responses, and a high margin of safety. Nanotechnology provides a multifunctional stage for the integration of desired adjuvant activities performed by the building blocks of tailor-designed nanoparticles. Using nanomaterials for antigen delivery can provide high bioavailability, sustained and controlled release profiles, and targeting and imaging properties resulting from manipulation of the nanomaterials’ physicochemical properties. Moreover, the inherent immune-regulating activity of particular nanomaterials can further promote and shape the cellular and humoral immune responses toward desired types. The combination of both the delivery function and immunomodulatory effect of nanomaterials as adjuvants is thought to largely benefit the immune outcomes of vaccination. In this review, we will address the current achievements of nanotechnology in the development of novel adjuvants. The potential mechanisms by which nanomaterials impact the immune responses to a vaccine and how physicochemical properties, including size, surface charge and surface modification, impact their resulting immunological outcomes will be discussed. This review aims to provide concentrated information to promote new insights for the development of novel vaccine adjuvants. PMID:25483497

  13. Adjuvant therapy after surgical stone management.

    PubMed

    Ferrandino, Michael N; Monga, Manoj; Preminger, Glenn M

    2009-01-01

    The aim of this article was to review the most widely researched adjuvant medical therapies for the surgical management of urolithiasis. Articles were identified and reviewed from PubMed and Medline databases with MeSH headings focusing on the various surgical treatments of urolithiasis and adjuvant therapy. Additional articles were retrieved from references and conference proceedings. Surgical treatments reviewed included shockwave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy. Adjuvant therapy was considered medical or complementary therapy as an adjunct to these surgical interventions. Adjuvant therapy for the surgical management of urolithiasis has been documented to increase stone-free rates, reduce stone remission rates, prevent renal damage, and decrease postoperative morbidity. A variety of agents have been studied, ranging from antioxidants to alpha-blockers and to alkalinizing agents. Additionally, there is increasing interest in complementary adjuvant therapy (ie, acupuncture). Adjuvant therapy is a fertile area for research in the surgical management of urolithiasis. The optimal agents have yet to be determined and therefore further investigation is warranted and necessary.

  14. Resistance detected by pyrosequencing following zidovudine monotherapy for prevention of HIV-1 mother-to-child-transmission.

    PubMed

    Olson, Scott C; Ngo-Giang-Huong, Nicole; Beck, Ingrid; Deng, Wenjie; Britto, Paula; Shapiro, David E; Bumgarner, Roger E; Mullins, James I; Van Dyke, Russell B; Jourdain, Gonzague; Frenkel, Lisa M

    2015-07-31

    To prevent mother-to-child-transmission of HIV-1, the 2010 WHO guidelines recommended prenatal zidovudine (ZDV) monotherapy (option A). To determine if ZDV monotherapy selects for HIV resistance in antiretroviral-naive women during pregnancy, specimens from 50 individuals were examined using pyrosequencing. ZDV-resistance mutations were detected at delivery in seven women (14%, 95% confidence interval 6.6-26.5%). These data raise the question whether women administered ZDV monotherapy for prevention of mother-to-child-transmission could have higher risk of virologic failure when later started on combination antiretroviral therapy, as has been demonstrated following single-dose nevirapine prophylaxis. PMID:26244386

  15. Adjuvant effects of saponins on animal immune responses*

    PubMed Central

    Rajput, Zahid Iqbal; Hu, Song-hua; Xiao, Chen-wen; Arijo, Abdullah G.

    2007-01-01

    Vaccines require optimal adjuvants including immunopotentiator and delivery systems to offer long term protection from infectious diseases in animals and man. Initially it was believed that adjuvants are responsible for promoting strong and sustainable antibody responses. Now it has been shown that adjuvants influence the isotype and avidity of antibody and also affect the properties of cell-mediated immunity. Mostly oil emulsions, lipopolysaccharides, polymers, saponins, liposomes, cytokines, ISCOMs (immunostimulating complexes), Freund’s complete adjuvant, Freund’s incomplete adjuvant, alums, bacterial toxins etc., are common adjuvants under investigation. Saponin based adjuvants have the ability to stimulate the cell mediated immune system as well as to enhance antibody production and have the advantage that only a low dose is needed for adjuvant activity. In the present study the importance of adjuvants, their role and the effect of saponin in immune system is reviewed. PMID:17323426

  16. Pharmacogenetics and breast cancer endocrine therapy: CYP2D6 as a predictive factor for tamoxifen metabolism and drug response?

    PubMed Central

    Stearns, Vered; Rae, James M.

    2011-01-01

    The identification of genetic polymorphisms that influence the efficacy and safety of therapies for breast cancer may allow future treatments to be individualised based not only on tumour characteristics but also on host genetics. Genetic factors that affect the metabolism, efficacy and safety of tamoxifen, one of the most common drugs used for the treatment and prevention of breast cancer, have received particular attention. Cytochrome P450 2D6 (CYP2D6) is crucial in the metabolism of tamoxifen to its active metabolite endoxifen. Women with genetic variants of CYP2D6 or who take drugs that inhibit the enzyme have low endoxifen plasma concentrations and may show reduced benefits to tamoxifen treatment. CYP2D6 polymorphisms and variants in other candidate genes may also influence secondary benefits and side effects of tamoxifen. Here, we summarise data suggesting that CYP2D6 status may be an important predictor of the benefits of tamoxifen to an individual; in addition, we briefly discuss the role of variants in other candidate genes. Whether CYP2D6 status should be determined prior to initiating tamoxifen therapy is currently under debate and may be appropriate only for select women who are candidates for tamoxifen alone but for whom alternative standard options are available. PMID:19019258

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

    SciTech Connect

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

    2009-03-13

    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.

  18. [Gemcitabine Monotherapy for Advanced Mycosis Fungoides--Two Case Reports and a Literature Review].

    PubMed

    Masuzawa, Mamiko; Takasu, Hiroshi; Amoh, Yasuyuki

    2015-12-01

    Gemcitabine, a pyrimidine nucleoside analogue, is gaining recognition as a potential therapeutic agent for advanced-stage and refractory cutaneous T-cell lymphoma (CTCL). We report of 2 patients whose advanced-stage mycosis fungoides was not sufficiently controlled by prior CHOP therapy. Both patients showed great improvement in the skin lesions with weekly gemcitabine therapy (1,000-1,200 mg/m2). The patients received four and 8 cycles of gemcitabine monotherapy, respectively, and no grade 3-4 hematological or hepatic adverse events occurred. This is the first report of the efficacy of gemcitabine for CTCL in Japan. Gemcitabine is well tolerated and is an effective monotherapy for CTCL. PMID:26809303

  19. Preferential pi-pi complexation between tamoxifen and borage oil/gamma linolenic acid: transcutaneous delivery and NMR spectral modulation.

    PubMed

    Heard, Charles M; Gallagher, Simon J; Congiatu, Costantino; Harwood, John; Thomas, Christopher P; McGuigan, Christopher; Nemcová, Marta; Nouskova, Tereza

    2005-09-30

    The effect of different proportions of borage oil on the in vitro transcutaneous delivery of tamoxifen were studied, with the aim of developing a gel capable of the simultaneous delivery of tamoxifen and gamma linolenic acid across (breast) skin. Supplementary work probed 1H NMR spectral data for tamoxifen in the presence of different proportions of polyunsaturated or unsaturated fatty acids. Typical, non-aqueous gels were modified to contain 1% tamoxifen and three levels of borage oil ( approximately 25% gamma linolenic acid) and the transcutaneous delivery of both tamoxifen and GLA across full thickness skin determined in vitro. Both tamoxifen and gamma linolenic acid permeated the skin with the ratio of moles being consistent at approximately 4:1. This was irrespective of time, amount of borage oil contained in the formulation (above a minimum) and the presence of other (unsaturated) excipients: mineral oil, Miglyiol 810N, white soft paraffin, PEG400 and Cabosil M5. Dose-dependent downfield shifts of tamoxifen aromatic protons were observed in the presence of borage oil and linolenic acid (gamma and alpha), but not saturated triacyl glycerol. The permeation data suggested vehicular complexation between tamoxifen and polyunsaturated constituents of borage oil and that such complexes permeated the skin intact. The 1H NMR data supported the hypothesis that such complexation was a consequence of preferential pi-pi orbital interactions between the phenyl groups of tamoxifen and the multiple double bonds of GLA. The mechanism for the permeation of intact complexes across skin remains to be elucidated. PMID:16115741

  20. Bilateral subthalamic stimulation monotherapy in advanced Parkinson's disease: long-term follow-up of patients.

    PubMed

    Valldeoriola, Francesc; Pilleri, Manuela; Tolosa, Eduardo; Molinuevo, José L; Rumià, Jordi; Ferrer, Enric

    2002-01-01

    Bilateral subthalamic nucleus stimulation (STN-DBS) is used to improve parkinsonian symptoms and attenuate levodopa-induced motor complications. In some patients, such clinical improvement allows antiparkinsonian medication (ApMed) withdrawal. We show the clinical outcome at the long-term follow-up of patients with advanced Parkinson's disease (PD) in which STN-DBS was used in monotherapy, and compare the clinical results of patients without medication with those obtained in parkinsonian patients in which ApMed were reduced but could not be totally displaced after surgery. We analyzed clinical outcome of ten patients with PD in which all ApMed was withdrawn after bilateral subthalamic stimulation and 16 parkinsonian patients still taking antiparkinsonian medication after surgery. After 1.5 years, STN-DBS monotherapy produced UPDRS motor scores similar to those observed in the on-drug condition before surgery without the inconvenience of motor fluctuations and dyskinesias. No significant differences were seen in most of clinical outcome measures when comparing patients still taking ApMed with patients in STN-DBS monotherapy but a few patients still taking ApMed presented mild dyskinesias and motor fluctuations and patients with STN-DBS monotherapy did not. STN-DBS is useful in the treatment of advanced PD and in some patients it is possible to maintain this therapy alone in the long term. The therapeutic effect of STN-DBS on motor signs can be equipotent to that of levodopa with the additional benefit of avoiding motor fluctuations and dyskinesias.

  1. Initial monotherapy and combination therapy and hypertension control the first year.

    PubMed

    Egan, Brent M; Bandyopadhyay, Dipankar; Shaftman, Stephanie R; Wagner, C Shaun; Zhao, Yumin; Yu-Isenberg, Kristina S

    2012-06-01

    Initial antihypertensive therapy with single-pill combinations produced more rapid blood pressure control than initial monotherapy in clinical trials. Other studies reported better cardiovascular outcomes in patients achieving lower blood pressure during the first treatment year. We assessed the effectiveness of initial antihypertensive monotherapy, free combinations, and single-pill combinations in controlling untreated, uncontrolled hypertensives during their first treatment year. Electronic record data were obtained from 180 practice sites; 106 621 hypertensive patients seen from January 2004 to June 2009 had uncontrolled blood pressure, were untreated for ≥ 6 months before therapy, and had ≥ 1 one-year follow-up blood pressure data. Control was determined by the first follow-up visit with blood pressure <140/<90 mm Hg for patients without diabetes mellitus or chronic kidney disease and <130/<80 mm Hg for patients with either or both conditions. Multivariable hazards regression ratios (HRs) and 95% CIs for time to control were calculated, adjusting for age, sex, baseline blood pressure, body mass index, diabetes mellitus, chronic kidney disease, cardiovascular disease, initial therapy, final blood pressure medication number, and therapeutic inertia. Patients on initial single-pill combinations (N = 9194) were more likely to have stage 2 hypertension than those on free combinations (N = 18 328) or monotherapy (N = 79 099; all P<0.001). Initial therapy with single-pill combinations (HR, 1.53 [95% CI, 1.47-1.58]) provided better hypertension control in the first year than free combinations (HR, 1.34; [95% CI, 1.31-1.37]) or monotherapy (reference) with benefits in black and white patients. Greater use of single-pill combinations as initial therapy may improve hypertension control and cardiovascular outcomes in the first treatment year.

  2. The Effects of Enzalutamide Monotherapy on Multiparametric 3T MR Imaging in Prostate Cancer.

    PubMed

    Van der Roest, Rosanne Cv; van Houdt, Petra J; Heijmink, Stijn Wtpj; de Jong, Jeroen; Bergman, André M; Zwart, Wilbert; van der Heide, Uulke A; van der Poel, Henk G

    2016-07-01

    The effects of enzalutamide monotherapy on prostate tumor downsizing and multiparametric MRI are currently unknown. Here we present the first case in literature of a patient with high-grade prostate cancer who underwent 3 months of neoadjuvant enzalutamide, for which the effects on mpMRI and histology were determined. Tumor size reduction and downstaging were noted. Neoadjuvant enzalutamide resulted in an increase in ADC value on the DWI-MRI sequences. Histological changes were also observed. PMID:27335799

  3. Beyond antigens and adjuvants: formulating future vaccines.

    PubMed

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

    2016-03-01

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

  4. Synthetic Self-Adjuvanting Glycopeptide Cancer Vaccines

    NASA Astrophysics Data System (ADS)

    Payne, Richard; McDonald, David; Byrne, Scott

    2015-10-01

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

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

    PubMed Central

    Chiu, Kuo-Liang; Chen, Tzu-Sheng; Chang, Shang-Miao; Yang, Shu-Yun; Chen, Li-Hsiou; Ni, Yung-Lun

    2015-01-01

    Introduction. Epidermal growth factor receptor (EGFR) mutations are known as oncogene driver mutations and with EGFR mutations exhibit good response to the EGFR tyrosine kinase inhibitor Gefitinib. Some studies have shown that activation of estrogen and estrogen receptor α or β (ERα/β) promote adenocarcinoma. We evaluated the relationship between the two receptors and the potential therapeutic benefit with Gefitinib and Tamoxifen. Methods. We assessed the association between EGFR mutations as well as ERα/β expression/location and overall survival in a cohort of 55 patients with LAC from a single hospital. PC9 (EGFR exon 19 deletion mutant; Gefitinib-vulnerable cells) and A549 (EGFR wild type; Gefitinib-resistant cells) cancer cells were used to evaluate the in vitro therapeutic benefits of combining Gefitinib and Tamoxifen. Results. We found that the cytosolic but not the nuclear expression of ERβ was associated with better OS in LAC tumors but not associated with EGFR mutation. The in vitro study showed that combined Gefitinib and Tamoxifen resulted in increased apoptosis and cytosolic expression of ERβ. In addition, combining both medications resulted in reduced cell growth and increased the cytotoxic effect of Gefitinib. Conclusion. Tamoxifen enhanced advanced LAC cytotoxic effect induced by Gefitinib by arresting ERβ in cytosol. PMID:25692143

  6. Tool Weighs Benefits, Risks of Raloxifene or Tamoxifen to Prevent Breast Cancer | Division of Cancer Prevention

    Cancer.gov

    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. |

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

    PubMed

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

    2015-08-01

    Recent clinical and imaging studies suggest that sex hormones modulate sexuality according to a psychophysiologic process of lateralization of the brain, with androgens playing a greater role in sexual functioning of left hemibrain/right handedness and estrogens possibly for right hemibrain/left handedness. Based on this perspective, the current study attempted to specify the relationship between hand preference, estrogens, and sexual function in subjects with male breast cancer, taking into account the sexual side effects of tamoxifen as the agent for inhibiting estrogen action. Twenty-eight Romanian men-17 right-handed and 11 left-handed-undergoing treatment with tamoxifen for male breast cancer participated in this study. These men were assessed both prior to and during tamoxifen treatment using the International Index of Erectile Function, a standardized instrument used for the evaluation of various aspects of sexual functioning, including erectile function (EF), orgasmic function (OF), sexual desire (SD), and overall functioning (OF). A main effect for handedness was found on EF, OF, SD, and OS scales, with right-handed men showing higher functioning than left-handed men. Regarding interaction effects, the left-handed group of men showed greater decreased sexual functioning during tamoxifen (on three subscales: OF, SD, OS) compared to right-handed men. Further research should be conducted in order to support and refine this potential lateralized process of sexual neuromodulation within the brain. PMID:26108899

  8. NF-kappa B inhibition markedly enhances sensitivity of resistant breast cancer tumor cells to tamoxifen.

    PubMed

    deGraffenried, L A; Chandrasekar, B; Friedrichs, W E; Donzis, E; Silva, J; Hidalgo, M; Freeman, J W; Weiss, G R

    2004-06-01

    Studies show that high Akt activity in breast carcinoma is associated with endocrine therapy resistance. Breast cancer cell lines expressing a constitutively active Akt are able to proliferate under reduced estrogen conditions, and are resistant to the growth inhibitory effects of tamoxifen. Understanding the targets of Akt signaling mediating tamoxifen resistance is of clinical significance. One possible target is nuclear factor kappa B (NF-kappa B), a transcription factor that plays a critical role in resistance to apoptosis and the induction of angiogenesis and invasion. In the present study, we found that Akt activity correlated with phosphorylation of I kappa B (the negative regulator of NF-kappa B), NF-kappa B DNA binding and tamoxifen resistance in vivo. Importantly, we found that co-treatment with the NF-kappa B inhibitor, parthenolide, or overexpression of I kappa B superrepressor restored tamoxifen sensitivity to our refractory Akt MCF-7 cells. These data suggest that activation of NF-kappa B via the PI3K/Akt signaling pathway may be a significant mechanism for development of endocrine therapy resistance in breast cancer, and that inhibition of NF-kappa B may be an effective treatment strategy to limit the progression of this disease.

  9. CYP2D6 Genotyping and Tamoxifen: An Unfinished Story in the Quest for Personalized Medicine

    PubMed Central

    de Souza, Jonas A.; Olopade, Olufunmilayo I.

    2011-01-01

    The philosophy behind personalized medicine is that each patient has a unique biologic profile that should guide the choice of therapy, resulting in an improved treatment outcome, ideally with reduced toxicity. Thus, there has been increasing interest in identifying genetic variations that are predictive of a drug’s efficacy or toxicity. Although it is one of the most effective drugs for treating breast cancer, tamoxifen is not effective in all estrogen receptor (ER)-positive breast cancer patients, and it is frequently associated with side effects, such as hot flashes. Relative resistance to tamoxifen treatment may be a result, in part, from impaired drug activation by cytochrome P450 2D6 (CYP2D6). Indeed, recent studies have identified allelic variations in CYP2D6 to be an important determinant of tamoxifen’s activity (and toxicity). This article will summarize the current information regarding the influence of the major genotypes and CYP2D6 inhibitors on tamoxifen metabolism, with a focus on its clinical utility and the current level of evidence for CYP2D6 genotyping of patients who are candidates for tamoxifen treatment. PMID:21421116

  10. Combination therapy using maxacalcitol and corticosteroid lotions preliminary to monotherapy with maxacalcitol lotion for scalp psoriasis.

    PubMed

    Okubo, Yukari; Natsume, Shoko; Usui, Kae; Muro, Mayuko; Tsuboi, Ryoji

    2014-02-01

    Topical treatment with betamethasone butyrate propionate lotion on 37 patients with scalp psoriasis was replaced with a combination therapy using maxacalcitol lotion (on weekdays) and BBP (on the weekends). This combination therapy was later switched to MXA monotherapy. To identify the optimum duration of the combination therapy, the patients were divided into two groups: a 4-week group and an 8-week group, which were given combination therapy and monotherapy. In both groups, the total mean scores for the skin symptoms had significantly improved in comparison with that obtained at the outset of the study (p < 0.01). In terms of overall improvement, 20.0% of the 4-week group and 72.7% of the 8-week group yielded scores reflecting moderate or greater improvement. The treatment administered to the 8-week group was significantly more effective than that given to the 4-week group at the end of the trial (p < 0.01). This study also suggests that a 4-week combination therapy is an option before switching to monotherapy, but that an 8-week therapy is preferable in severe cases.

  11. Health technology assessment in the HIV setting: the case of monotherapy.

    PubMed

    Restelli, Umberto; Croce, Davide; Porazzi, Emanuele; Scolari, Francesca; Bonfanti, Marzia; Galli, Massimo; Gianotti, Nicola; Rizzardini, Giuliano; Garagiola, Elisabetta; Vanzago, Anna; Foglia, Emanuela

    2014-07-01

    Despite the success of multiple-drug therapy regimens, the idea of treating human immunodeficiency virus (HIV) infection with fewer drugs is captivating due to issues of convenience, long-term toxicities and costs. This study investigated the impact on a local health budget of the introduction of a protease inhibitor (PI)-based antiretroviral monotherapy. An analysis of 23,721 administrative records of HIV-infected patients and a health technology assessment (HTA) were performed to assess cost-effectiveness, budget, organizational, ethics, and equity impact. Data showed that monotherapy had a annual cost of € 7,076 (patient with undetectable viral load) and € 7,860 (patient with detectable viral load), and that its implementation would realise economic savings of between 12 and 24 million euro (between 4.80% and 9.72% of the 2010 total regional budget expenditure for HIV management) in the first year, with cumulated savings of between 48 and 145 million euro over the following five years. Organizational, ethical and equity impact did not indicate any significant differences. The study suggests that for specific categories of patients monotherapy may be an alternative to existing therapies. Its implementation would not result in higher operating costs, and would lead to a reduction in total expenditure. PMID:25180841

  12. Regulation of p130Cas/BCAR1 Expression in Tamoxifen-Sensitive and Tamoxifen-Resistant Breast Cancer Cells by EGR1 and NAB21

    PubMed Central

    Kumbrink, Joerg; Kirsch, Kathrin H

    2012-01-01

    Elevated levels of p130Cas/BCAR1 (Crk-associated substrate/breast cancer antiestrogen resistance 1) are found in aggressive breast tumors and are associated with tamoxifen resistance of mammary cancers. p130Cas promotes the integration of protein complexes involved in multiple signaling pathways frequently deregulated in breast cancer. To elucidate mechanisms leading to p130Cas up-regulation in mammary carcinomas and during acquired tamoxifen resistance, the regulation of p130Cas/BCAR1 was studied. Because multiple putative binding motifs for the inducible transcription factor EGR1 were identified in the 5′ region of BCAR1, the p130Cas/BCAR1 regulation by EGR1 and its coregulator NAB2 was investigated. Overexpression or short interfering RNA (siRNA)-mediated down-regulation of EGR1 or NAB2, and chromatin immunoprecipitations indicated that EGR1 and NAB2 act in concert to positively regulate p130Cas/BCAR1 expression in breast cancer cells. p130Cas depletion using siRNA showed that, in tamoxifen-sensitive MCF-7 cells, p130Cas regulates EGR1 and NAB2 expression, whereas in the derivative tamoxifen-resistant TAM-R cells, only NAB2 levels were influenced. BCAR1 messenger RNA and p130Cas protein were upregulated by phorbol esters following the kinetics of late response genes in MCF-7 but not in TAM-R cells. Thus, in MCF-7 cells, we identified a positive feedback loop where p130Cas positively regulates EGR1 and NAB2, which in turn induce p130Cas expression. Importantly, compared with MCF-7, enhanced NAB2 expression and increased EGR1 binding to the BCAR1 5′ region observed in TAM-R may lead to the constitutively increased p130Cas/BCAR1 levels in TAM-R cells. The uncovered differences in this EGR1/NAB2/p130Cas network in MCF-7 versus TAM-R cells may also contribute to p130Cas up-regulation during acquired tamoxifen resistance. PMID:22431919

  13. Oil-based emulsion vaccine adjuvants.

    PubMed

    Schijns, Virgil E J C; Strioga, Marius; Ascarateil, Stephane

    2014-01-01

    Vaccine adjuvants are critical components in experimental and licensed vaccines used in human and veterinary medicine. When aiming to evoke an immune response to a purified antigen, the administration of antigen alone is often insufficient, unless the antigen contains microbial structures or has a natural particulate structure. In most cases, the rationale to use an adjuvant is obvious to the experimental immunologist or the professional vaccinologist, who is familiar with the nature of the antigen, and the aim of the vaccine to elicit a specific antibody response and/or a specific type of T cell response. In this unit, we describe protocols to formulate antigens with oil-based emulsions. Such emulsions represent a major prototype adjuvant category that is frequently used in experimental preclinical vaccines, as well as veterinary and human vaccines.

  14. Highly sensitive simultaneous quantification of estrogenic tamoxifen metabolites and steroid hormones by LC-MS/MS.

    PubMed

    Johänning, Janina; Heinkele, Georg; Precht, Jana C; Brauch, Hiltrud; Eichelbaum, Michel; Schwab, Matthias; Schroth, Werner; Mürdter, Thomas E

    2015-09-01

    Tamoxifen is a mainstay in the treatment of estrogen receptor-positive breast cancer and is metabolized to more than 30 different compounds. Little is known about in vivo concentrations of estrogenic metabolites E-metabolite E, Z-metabolite E, and bisphenol and their relevance for tamoxifen efficacy. Therefore, we developed a highly sensitive HPLC-ESI-MS/MS quantification method for tamoxifen metabolites bisphenol, E-metabolite E, and Z-metabolite E as well as for the sex steroid hormones estradiol, estrone, testosterone, androstenedione, and progesterone. Plasma samples were subjected to protein precipitation followed by solid phase extraction. Upon derivatization with 3-[(N-succinimide-1-yl)oxycarbonyl]-1-methylpyridinium iodide, all analytes were separated on a sub-2-μm column with a gradient of acetonitrile in water with 0.1 % of formic acid. Analytes were detected on a triple-quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction monitoring mode. Our method demonstrated high sensitivity, accuracy, and precision. The lower limits of quantification were 12, 8, and 25 pM for bisphenol, E-metabolite E, and Z-metabolite E, respectively, and 4 pM for estradiol and estrogen, 50 pM for testosterone and androstenedione, and 25 pM for progesterone. The method was applied to plasma samples of postmenopausal patients taken at baseline and under tamoxifen therapy. Graphical Abstract Sample preparation and derivatization for highly sensitive quantification of estrogenic tamoxifen metabolites and steroid hormones by HPLC-MS/MS.

  15. Synthesis and biological evaluation of novel tamoxifen-1,2,4-triazole conjugates.

    PubMed

    Murty, M S R; Katiki, Mohana Rao; Nanubolu, Jagadeesh Babu; Garimella, Srujana; Polepalli, Sowjanya; Jain, Nishant; Buddana, Sudheer Kumar; Prakasham, R S

    2016-08-01

    A new class of compounds, structurally related to the breast cancer drug tamoxifen, was designed and synthesized. The McMurry coupling reaction was used as the key synthetic step in the preparation of these analogs, and the structural assignments were made on the basis of [Formula: see text] NMR, [Formula: see text] NMR, and HRMS studies. The absolute stereochemistry of E and Z isomers was unambiguously confirmed by a single-crystal X-ray diffraction analysis. Water was found to be an inexpensive nontoxic and effective medium for the C-N bond formation. Utilizing this protocol, various tamoxifen derivatives were synthesized in good yields. Environmental acceptability, low cost, and high yields are the important features of this protocol. These compounds were evaluated for their antiproliferative activity on five human tumor cell lines. Compound 4p ([Formula: see text]) showed improved antiproliferative activity against breast cancer cell line (MDA-MB-231) compared to tamoxifen ([Formula: see text]), while the compound 4o ([Formula: see text]) exhibited similar activity against SiHa compared to the reference drug, tamoxifen ([Formula: see text]). In addition, these analogs were investigated for their antibacterial activity against six bacterial strains. Preliminary results indicate that some of the newly synthesized title compounds exhibited promising antibacterial activity compared with the standard drug, vancomycin. A new class of compounds were designed rationally by the replacement of a ethyl group in tamoxifen with a methylene (1H-1,2,4-triazole) group. The absolute stereochemistry of E and Z isomers were unambiguously confirmed by a single-crystal X-ray diffraction analysis. The title compounds were evaluated for their antiproliferative and antibacterial activities.

  16. Synthesis and biological evaluation of novel tamoxifen-1,2,4-triazole conjugates.

    PubMed

    Murty, M S R; Katiki, Mohana Rao; Nanubolu, Jagadeesh Babu; Garimella, Srujana; Polepalli, Sowjanya; Jain, Nishant; Buddana, Sudheer Kumar; Prakasham, R S

    2016-08-01

    A new class of compounds, structurally related to the breast cancer drug tamoxifen, was designed and synthesized. The McMurry coupling reaction was used as the key synthetic step in the preparation of these analogs, and the structural assignments were made on the basis of [Formula: see text] NMR, [Formula: see text] NMR, and HRMS studies. The absolute stereochemistry of E and Z isomers was unambiguously confirmed by a single-crystal X-ray diffraction analysis. Water was found to be an inexpensive nontoxic and effective medium for the C-N bond formation. Utilizing this protocol, various tamoxifen derivatives were synthesized in good yields. Environmental acceptability, low cost, and high yields are the important features of this protocol. These compounds were evaluated for their antiproliferative activity on five human tumor cell lines. Compound 4p ([Formula: see text]) showed improved antiproliferative activity against breast cancer cell line (MDA-MB-231) compared to tamoxifen ([Formula: see text]), while the compound 4o ([Formula: see text]) exhibited similar activity against SiHa compared to the reference drug, tamoxifen ([Formula: see text]). In addition, these analogs were investigated for their antibacterial activity against six bacterial strains. Preliminary results indicate that some of the newly synthesized title compounds exhibited promising antibacterial activity compared with the standard drug, vancomycin. A new class of compounds were designed rationally by the replacement of a ethyl group in tamoxifen with a methylene (1H-1,2,4-triazole) group. The absolute stereochemistry of E and Z isomers were unambiguously confirmed by a single-crystal X-ray diffraction analysis. The title compounds were evaluated for their antiproliferative and antibacterial activities. PMID:27278444

  17. Highly sensitive simultaneous quantification of estrogenic tamoxifen metabolites and steroid hormones by LC-MS/MS.

    PubMed

    Johänning, Janina; Heinkele, Georg; Precht, Jana C; Brauch, Hiltrud; Eichelbaum, Michel; Schwab, Matthias; Schroth, Werner; Mürdter, Thomas E

    2015-09-01

    Tamoxifen is a mainstay in the treatment of estrogen receptor-positive breast cancer and is metabolized to more than 30 different compounds. Little is known about in vivo concentrations of estrogenic metabolites E-metabolite E, Z-metabolite E, and bisphenol and their relevance for tamoxifen efficacy. Therefore, we developed a highly sensitive HPLC-ESI-MS/MS quantification method for tamoxifen metabolites bisphenol, E-metabolite E, and Z-metabolite E as well as for the sex steroid hormones estradiol, estrone, testosterone, androstenedione, and progesterone. Plasma samples were subjected to protein precipitation followed by solid phase extraction. Upon derivatization with 3-[(N-succinimide-1-yl)oxycarbonyl]-1-methylpyridinium iodide, all analytes were separated on a sub-2-μm column with a gradient of acetonitrile in water with 0.1 % of formic acid. Analytes were detected on a triple-quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction monitoring mode. Our method demonstrated high sensitivity, accuracy, and precision. The lower limits of quantification were 12, 8, and 25 pM for bisphenol, E-metabolite E, and Z-metabolite E, respectively, and 4 pM for estradiol and estrogen, 50 pM for testosterone and androstenedione, and 25 pM for progesterone. The method was applied to plasma samples of postmenopausal patients taken at baseline and under tamoxifen therapy. Graphical Abstract Sample preparation and derivatization for highly sensitive quantification of estrogenic tamoxifen metabolites and steroid hormones by HPLC-MS/MS. PMID:26206706

  18. Tamoxifen administration routes and dosage for inducible Cre-mediated gene disruption in mouse hearts.

    PubMed

    Andersson, Kristin B; Winer, Lisbeth H; Mørk, Halvor K; Molkentin, Jeffery D; Jaisser, Frédéric

    2010-08-01

    Tissue-specific and time-dependent control of in vivo gene disruption may be achieved using conditional knockout strategies in transgenic mice. Fusion of mutant estrogen receptor ligand-binding domains to Cre recombinase (Cre-ER(T), MerCreMer) combined with cardiac-directed gene expression has been used to generate several cardiac-specific tamoxifen-inducible Cre-expressing mouse lines. Such mice have successfully been used to generate Cre-loxP-mediated gene disruption in an inducible manner in the myocardium in vivo. However, information is sparse regarding the tamoxifen dosage, the time course of gene disruption and whether different administration routes differ in efficiency in obtaining gene disruption in the myocardium. We have evaluated these parameters in Serca2 ( flox/flox ) Tg(alphaMHC-MerCreMer) transgenic mice (SERCA2 KO). Serca2 mRNA transcript abundance was used as a sensitive indicator of Cre-loxP-dependent gene disruption in the myocardium. We found that 2 i.p. injections of tamoxifen in oil (1 mg/day, approximate total dose 80 mg/kg) was sufficient for efficient gene disruption with maximal reduction of Serca2 mRNA as early as 4 days after tamoxifen induction. Moreover, a simple protocol using tamoxifen-supplemented non-pelleted dry feed p.o. was comparable to i.p. injections in inducing gene disruption. These improvements may significantly improve animal welfare and reduce the workload in the production of cardiac conditional knockout mice.

  19. Breast density measurements using ultrasound tomography for patients undergoing tamoxifen treatment

    NASA Astrophysics Data System (ADS)

    Sak, Mark; Duric, Neb; Littrup, Peter; Li, Cuiping; Bey-Knight, Lisa; Sherman, Mark; Boyd, Norman; Gierach, Gretchen

    2013-03-01

    Women with high breast density have an increased risk of developing breast cancer. Women treated with the selective estrogen receptor modulator tamoxifen for estrogen receptor positive breast cancer experience a 50% reduction in risk of contralateral breast cancer and overall reduction of similar magnitude has been identified among high-risk women receiving the drug for prevention. Tamoxifen has been shown to reduce mammographic density, and in the IBIS-1 chemoprevention trial, risk reduction and decline in density were significantly associated. Ultrasound tomography (UST) is an imaging modality that can create tomographic sound speed images of the breast. These sound speed images are useful because breast density is proportional to sound speed. The aim of this work is to examine the relationship between USTmeasured breast density and the use of tamoxifen. So far, preliminary results for a small number of patients have been observed and are promising. Correlations between the UST-measured density and mammographic density are strong and positive, while relationships between UST density with some patient specific risk factors behave as expected. Initial results of UST examinations of tamoxifen treated patients show that approximately 45% of the patients have a decrease in density in the contralateral breast after only several months of treatment. The true effect of tamoxifen on UST-measured density cannot yet be fully determined until more data are collected. However, these promising results suggest that UST can be used to reliably assess quantitative changes in breast density over short intervals and therefore suggest that UST may enable rapid assessment of density changes associated with therapeutic and preventative interventions.

  20. Development and characterization of a tamoxifen-resistant breast carcinoma xenograft.

    PubMed

    Naundorf, H; Becker, M; Lykkesfeldt, A E; Elbe, B; Neumann, C; Büttner, B; Fichtner, I

    2000-06-01

    A human tamoxifen-resistant mammary carcinoma, MaCa 3366/TAM, originating from a sensitive parental xenograft 3366 was successfully established by treatment of tumour-bearing nude mice with 1-50 mg kg(-1) tamoxifen for 3 years during routine passaging. Both tumours did not differ significantly in OR- and PR-positivity, however, when compared with the sensitive tumour line, the mean OR content of the TAM-resistant subline is slightly lower. An OR-upregulation following withdrawal of oestradiol treatment was observed in the parental tumours but not in the resistant xenografts. Following long-term treatment with tamoxifen, the histological pattern of the breast carcinoma changed. The more differentiated structures being apparent after treatment with 17beta-oestradiol in the original 3366 tumour were not induced in the resistant line. Tamoxifen failed to induce a tumour growth inhibition in comparison to the tamoxifen-sensitive line. The pure anti-oestrogen, ICI 182 780, revealed cross-resistance. Sequence analysis of the hormone-binding domain of the OR of both lines showed no differences, suggesting that either mutations in other regions of the OR are involved in the TAM-resistance phenotype or that mechanisms outside of this protein induced this phenotype. Oestrogen and anti-oestrogen regulate pS2 and cathepsin D expression in 3366 tumours as in the human breast cancer cell line MCF-7. The resistant 3366/TAM tumours have lost this regulation. The established breast cancer xenografts 3366 and 3366/TAM offer the possibility of investigating mechanisms of anti-oestrogen resistance in an in vivo situation. They can be used to test novel approaches to prevent, or to overcome, this resistance in a clinically related manner. PMID:10839300

  1. Differences in estrogen and progesterone receptor expression in endometrial polyps and atrophic endometrium of postmenopausal women with and without exposure to tamoxifen

    PubMed Central

    LEÃO, ROGERIO BARROS FERREIRA; ANDRADE, LILIANA; VASSALO, JOSE; ANTUNES, ARMANDO; PINTO-NETO, AARÃO; COSTA-PAIVA, LUCIA

    2013-01-01

    Postmenopausal women who use tamoxifen present with an increased incidence of endometrial alterations, such as polyps and hyperplasia, in addition to a higher risk of malignant endometrial neoplasms. Among these endometrial changes, polyps are the most common, with a pathogenesis associated with hormonal influence. The objective of this study was to compare the expression of estrogen receptors (ERs) and progesterone receptors (PRs) in endometrial polyps from tamoxifen users with that in endometrial polyps and the atrophic endometrium of postmenopausal tamoxifen non-users. Among women undergoing surgical hysteroscopy, 84 tamoxifen users with benign endometrial polyps were selected. This group was compared to 84 samples of atrophic endometrium and to 252 benign polyps from postmenopausal women who were not treated with tamoxifen. The expression of ER/PR was assessed by immunohistochemical analysis, according to the percentage of stained cells, intensity of nuclear staining and final score. The polyps from tamoxifen users exhibited a higher expression of ER and PR in the glandular epithelium and stroma compared to the atrophic endometrium (P<0.0001). Compared to the polyps from women not treated with tamoxifen, tamoxifen users exhibited a higher PR expression in the epithelium (P=0.0014) and stroma (P=0.0056), with no difference in the expression of ER. In conclusion, endometrial polyps frequently exhibit an increase in ER expression, regardless of tamoxifen use. High levels of PR expression appear to be consistent with the estrogen agonist effects of tamoxifen. PMID:24649292

  2. Adjuvants and vector systems for allergy vaccines.

    PubMed

    Moingeon, Philippe; Lombardi, Vincent; Saint-Lu, Nathalie; Tourdot, Sophie; Bodo, Véronique; Mascarell, Laurent

    2011-05-01

    Allergen-specific immunotherapy represents a curative treatment of type I allergies. Subcutaneous immunotherapy is conducted with allergens adsorbed on aluminum hydroxide or calcium phosphate particles, whereas sublingual immunotherapy relies on high doses of soluble allergen without any immunopotentiator. There is a potential benefit of adjuvants enhancing regulatory and Th1 CD4+T cell responses during specific immunotherapy. Molecules affecting dendritic cells favor the induction of T regulatory cell and Th1 responses and represent valid candidate adjuvants for allergy vaccines. Furthermore, the interest in viruslike particles and mucoadhesive particulate vector systems, which may better address the allergen(s) to tolerogenic antigen-presenting cells, is documented.

  3. [ADJUVANTED INFLUENZA VACCINES: DATA FROM DIRECT COMPARATIVE STUDIES].

    PubMed

    Chernikova, M I; Vasiliev, Yu M

    2015-01-01

    Vaccines are the cornerstone of influenza control, however available vaccines are subject to certain limitations. Adjuvanted vaccines are a promising approach, however available adjuvants have a suboptimal effectiveness and safety profile. Data from direct comparative trials are necessary for selection of optimal adjuvants among currently available and search for novel safe and effective adjuvants for next generation influenza vaccines. Data from published direct comparative studies of adjuvants for influenza vaccines are summarized, a lack of such studies is noted, especially those using adequate methods and designs and comparing adjuvants of major groups (nature/source and mechanism of action). Several promising approaches of adjuvant research and development could be identified: chitosan-based adjuvants, oil-in-water emulsions and multi-component formulations (depot + immune modulating components).

  4. Outlining novel cellular adjuvant products for therapeutic vaccines against cancer.

    PubMed

    Tefit, Josianne Nitcheu; Serra, Vincent

    2011-08-01

    Despite the library of new adjuvants available for use in vaccines, we remain, at present, almost reliant on aluminum-based compounds for clinical use. The increasing use of recombinant subunit vaccines, however, makes the need for improved adjuvant of particular interest. Adjuvants are crucial components of all cancer vaccines whether they are composed of whole cells, proteins or peptides. For the purposes of this article, cellular adjuvant products are defined as adjuvants associated with cellular or T-cell immunity. Several pharmaceutical companies are developing new adjuvants or immune enhancers for the treatment of cancers such as melanoma and non-small-cell lung carcinoma. Several products are being developed and have entered clinical trials either alone or in combination. In this article, we discuss recent adjuvant development and novel cellular adjuvant products for therapeutic cancer vaccines.

  5. Simultaneous permeation of tamoxifen and gamma linolenic acid across excised human skin. Further evidence of the permeation of solvated complexes.

    PubMed

    Karia, Clare; Harwood, John L; Morris, Andy P; Heard, Charles M

    2004-03-01

    Tamoxifen is the hormonal treatment of choice in women who have hormone-dependent breast cancer and its efficacy in those women considered to have a high risk of developing breast cancer, has also been established. Gamma linolenic acid (GLA) has been shown to decrease the invasion of breast cancer and recent studies have demonstrated that GLA can enhance the oestrogen receptor down-regulation induced by tamoxifen. However, tamoxifen is associated with serious side-effects due mainly to systemic delivery, and targeted delivery of both tamoxifen and GLA would be highly beneficial. This work was a preliminary study for the development of a transcutaneous system to simultaneously deliver both tamoxifen and GLA directly to the breast. Full thickness human skin was dosed with 500 microl saturated solution of tamoxifen in borage oil (25% GLA) and the simultaneous permeation of the two actives determined. There was rapid flux with minimal lag time, the cumulative permeation at 24 h was 764.3 +/- 94.2 microg cm(-2) for GLA and 5.44 +/- 0.67 microg cm(-2) for tamoxifen: the latter being comparable to the amount of tamoxifen associated with cancerous breast tissue from a 20 mg oral dose. The ratio of GLA/tamoxifen permeated at different timepoints was quite consistent, both in terms of mass (mean 138, S.D. 15.1) and mols (mean 184, S.D. 20.3). It was determined that 2.5 molecules of GLA were associated with each molecule of tamoxifen in the permeation process, equating to a solvation cage of three molecules of triacylglycerol. This study has demonstrated the feasibility of administering simultaneously tamoxifen and GLA using borage oil as vehicle, which warrants further investigation as a novel topical two-component system in relation to or prophylaxis of those perceived at high risk of developing breast cancer. The study also provides further evidence of the permeation of solvated complexes across skin, rather than discrete penetrant molecules. PMID:15129999

  6. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Adjuvants for pesticide use dilutions. 172.710... HUMAN CONSUMPTION Other Specific Usage Additives § 172.710 Adjuvants for pesticide use dilutions. The following surfactants and related adjuvants may be safely added to pesticide use dilutions by a grower...

  7. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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

  8. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

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

  9. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Adjuvants for pesticide use dilutions. 172.710... HUMAN CONSUMPTION Other Specific Usage Additives § 172.710 Adjuvants for pesticide use dilutions. The following surfactants and related adjuvants may be safely added to pesticide use dilutions by a grower...

  10. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001 (c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 182.99...

  11. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Adjuvants for pesticide chemicals. 582.99...

  12. Gaps in knowledge and prospects for research of adjuvanted vaccines.

    PubMed

    Seder, Robert; Reed, Steven G; O'Hagan, Derek; Malyala, Padma; D'Oro, Ugo; Laera, Donatello; Abrignani, Sergio; Cerundolo, Vincenzo; Steinman, Lawrence; Bertholet, Sylvie

    2015-06-01

    A panel of researchers working in different areas of adjuvanted vaccines deliberated over the topic, "Gaps in knowledge and prospects for research of adjuvanted vaccines" at, "Enhancing Vaccine Immunity and Value" conference held in July 2014. Several vaccine challenges and applications for new adjuvant technologies were discussed.

  13. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 582.99...

  14. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 182.99...

  15. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Adjuvants for pesticide chemicals. 582.99...

  16. 21 CFR 582.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... § 582.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.1001(c) and (d), which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Adjuvants for pesticide chemicals. 582.99...

  17. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) SUBSTANCES GENERALLY RECOGNIZED AS SAFE General Provisions § 182.99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Adjuvants for pesticide chemicals. 182.99...

  18. 21 CFR 182.99 - Adjuvants for pesticide chemicals.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ....99 Adjuvants for pesticide chemicals. Adjuvants, identified and used in accordance with 40 CFR 180.910 and 40 CFR 180.920, which are added to pesticide use dilutions by a grower or applicator prior to... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Adjuvants for pesticide chemicals. 182.99...

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

    SciTech Connect

    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.

  20. Adjuvant Chemotherapy in Rectal Cancer after Chemoradiotherapy.

    PubMed

    Boustani, J; Caubet, M; Bosset, J-F

    2016-02-01

    The aim of this overview was to investigate whether adjuvant chemotherapy has a favourable effect on the outcome of patients with rectal cancer who had preoperative (chemo)radiotherapy. A review of randomised clinical trials that allocated patients between fluorouracil-based and observation or between fluorouracil-based and oxaliplatin-based adjuvant chemotherapy after preoperative (chemo)radiotherapy was carried out, including their corresponding meta-analyses. None of the five randomised trials has shown a significant benefit of fluorouracil-based adjuvant chemotherapy for overall survival or disease-free survival. Also, the three corresponding meta-analyses failed to show a benefit of adjuvant treatment. Of three randomised trials - two phase III and one phase II with a 3-year disease-free survival end point - two showed a small benefit of adding oxaliplatin to fluorouracil, one failed. The corresponding meta-analyses showed that the pooled difference was not significant. In conclusion, the use of postoperative 5-fluorouracil-based chemotherapy with or without oxaliplatin in patients with rectal cancer after preoperative (chemo)radiotherapy is not scientifically proven.

  1. Adjuvants for peptide-based cancer vaccines.

    PubMed

    Khong, Hiep; Overwijk, Willem W

    2016-01-01

    Cancer therapies based on T cells have shown impressive clinical benefit. In particular, immune checkpoint blockade therapies with anti-CTLA-4 and anti-PD-1/PD-L1 are causing dramatic tumor shrinkage and prolonged patient survival in a variety of cancers. However, many patients do not benefit, possibly due to insufficient spontaneous T cell reactivity against their tumors and/or lacking immune cell infiltration to tumor site. Such tumor-specific T cell responses could be induced through anti-cancer vaccination; but despite great success in animal models, only a few of many cancer vaccine trials have demonstrated robust clinical benefit. One reason for this difference may be the use of potent, effective vaccine adjuvants in animal models, vs. the use of safe, but very weak, vaccine adjuvants in clinical trials. As vaccine adjuvants dictate the type and magnitude of the T cell response after vaccination, it is critical to understand how they work to design safe, but also effective, cancer vaccines for clinical use. Here we discuss current insights into the mechanism of action and practical application of vaccine adjuvants, with a focus on peptide-based cancer vaccines. PMID:27660710

  2. Adjuvant and Definitive Radiotherapy for Adrenocortical Carcinoma

    SciTech Connect

    Sabolch, Aaron; Feng, Mary; Griffith, Kent; Hammer, Gary; Doherty, Gerard; Ben-Josef, Edgar

    2011-08-01

    Purpose: To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma. Methods and Materials: Outcomes were analyzed from 58 patients with 64 instances of treatment for adrenocortical carcinoma at the University of Michigan's Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these instances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival. Results: Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030). Conclusions: Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection.

  3. Induction of lupus autoantibodies by adjuvants

    USGS Publications Warehouse

    Satoh, M.; Kuroda, Y.; Yoshida, H.; Behney, K.M.; Mizutani, A.; Akaogi, J.; Nacionales, D.C.; Lorenson, T.D.; Rosenbauer, R.J.; Reeves, W.H.

    2003-01-01

    Exposure to the hydrocarbon oil pristane induces lupus specific autoantibodies in non-autoimmune mice. We investigated whether the capacity to induce lupus-like autoimmunity is a unique property of pristane or is shared by other adjuvant oils. Seven groups of 3-month-old female BALB/cJ mice received a single intraperitoneal injection of pristane, squalene (used in the adjuvant MF59), incomplete Freund's adjuvant (IFA), three different medicinal mineral oils, or saline, respectively. Serum autoantibodies and peritoneal cytokine production were measured. In addition to pristane, the mineral oil Bayol F (IFA) and the endogenous hydrocarbon squalene both induced anti-nRNP/Sm and -Su autoantibodies (20% and 25% of mice, respectively). All of these hydrocarbons had prolonged effects on cytokine production by peritoneal APCs. However, high levels of IL-6, IL-12, and TNF?? production 2-3 months after intraperitoneal injection appeared to be associated with the ability to induce lupus autoantibodies. The ability to induce lupus autoantibodies is shared by several hydrocarbons and is not unique to pristane. It correlates with stimulation of the production of IL-12 and other cytokines, suggesting a relationship with a hydrocarbon's adjuvanticity. The potential to induce autoimmunity may complicate the use of oil adjuvants in human and veterinary vaccines. ?? 2003 Elsevier Ltd. All rights reserved.

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

    PubMed

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

    2015-11-15

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

  5. Bioconcentration of (15)N-tamoxifen at environmental concentration in liver, gonad and muscle of Danio rerio.

    PubMed

    Orias, Frédéric; Simon, Laurent; Mialdea, Gladys; Clair, Angéline; Brosselin, Vanessa; Perrodin, Yves

    2015-10-01

    Pharmaceutical compounds (PCs) are ubiquitous in aquatic ecosystems. In addition to the direct ecotoxicological risk presented by certain PCs, others can accumulate inside organisms and along trophic webs, subsequently contaminating whole ecosystems. We studied the bioconcentration of a bioaccumulative PC already found several times in the environment: tamoxifen. To this end, we exposed Danio rerio for 21d to (15)N-tamoxifen concentrations ranging from 0.1 to 10µg/L and used an analytic method based on stable isotopes to evaluate the tamoxifen content in these organisms. The evolution of the (15)N/(14)N ratio was thus measured in liver, muscle and gonads of exposed fish compared to control fish. We succeeded in quantifying (15)N-tamoxifen bioconcentrations at all the exposure concentrations tested. The highest bioconcentration factors of tamoxifen measured were 14,920 in muscle, 73,800 in liver and 85,600 in gonads of fish after 21d exposure at a nominal concentration of 10µg/L. However, these bioconcentration factors have to be considered as maximal values (BCFMAX). Indeed, despite its proven stability, tamoxifen can be potentially partially degraded during experiments. We now need to refine these results by using a direct analytic method (i.e. LC-MS/MS). PMID:26163873

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

    PubMed Central

    Ye, Risheng; Wang, Qiong A.; Tao, Caroline; Vishvanath, Lavanya; Shao, Mengle; McDonald, Jeffery G.; Gupta, Rana K.; Scherer, Philipp E.

    2015-01-01

    Background The selective estrogen receptor modulator tamoxifen, in combination with the Cre-ERT2 fusion protein, has been one of the mainstream methods to induce genetic recombination and has found widespread application in lineage tracing studies. Methods & results Here, we report that tamoxifen exposure at widely used concentrations remains detectable by mass-spectrometric analysis in adipose tissue after a washout period of 10 days. Surprisingly, its ability to maintain nuclear translocation of the Cre-ERT2 protein is preserved beyond 2 months of washout. Tamoxifen treatment acutely leads to transient lipoatrophy, followed by de novo adipogenesis that reconstitutes the original fat mass. In addition, we find a “synthetically lethal” phenotype for adipocytes when tamoxifen treatment is combined with adipocyte-specific loss-of-function mutants, such as an adipocyte-specific PPARγ knockout. This is observed to a lesser extent when alternative inducible approaches are employed. Conclusions These findings highlight the potential for tamoxifen-induced adipogenesis, and the associated drawbacks of the use of tamoxifen in lineage tracing studies, explaining the discrepancy in lineage tracing results from different systems with temporal control of gene targeting. PMID:26629402

  7. Drug Efflux Transporters Are Overexpressed in Short-Term Tamoxifen-Induced MCF7 Breast Cancer Cells.

    PubMed

    Krisnamurti, Desak Gede Budi; Louisa, Melva; Anggraeni, Erlia; Wanandi, Septelia Inawati

    2016-01-01

    Tamoxifen is the first line drug used in the treatment of estrogen receptor-positive (ER+) breast cancer. The development of multidrug resistance (MDR) to tamoxifen remains a major challenge in the treatment of cancer. One of the mechanisms related to MDR is decrease of drug influx via overexpression of drug efflux transporters such as P-glycoprotein (P-gp/MDR1), multidrug resistance associated protein (MRP), or BCRP (breast cancer resistance protein). We aimed to investigate whether the sensitivity of tamoxifen to the cells is maintained through the short period and whether the expressions of several drug efflux transporters have been upregulated. We exposed MCF7 breast cancer cells with tamoxifen 1 μM for 10 passages (MCF7 (T)). The result showed that MCF7 began to lose their sensitivity to tamoxifen from the second passage. MCF7 (T) also showed a significant increase in all transporters examined compared with MCF7 parent cells. The result also showed a significant increase of CC50 in MCF7 (T) compared to that in MCF7 (97.54 μM and 3.04 μM, resp.). In conclusion, we suggest that the expression of several drug efflux transporters such as P-glycoprotein, MRP2, and BCRP might be used and further studied as a marker in the development of tamoxifen resistance. PMID:26981116

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

    PubMed

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

    2003-12-01

    1. An increased incidence of systemic hypertension has been documented in postmenopausal women and identified as an independent risk factor in the development of cerebrovascular stroke. The present study examined whether cerebrovascular reactivity was increased in the hypertensive ovariectomized rat, and explored the potential therapeutic benefit of the partial estrogen receptor agonist tamoxifen. 2. Female Sprague-Dawley rats were subjected to bilateral ovariectomy (OVX, n=16) or a sham operation (n=8). At 6-week postsurgery, rats were anesthetized to assess ventricular contractility and blood pressure. In a second series of experiments, OVX rats (n=8) were given tamoxifen starting 3 weeks postsurgery, and continued for 3 weeks. At the end of each protocol, the middle cerebral artery was harvested and rings were mounted in wire-myographs to measure isometric tension. 3. Systolic arterial pressure (SAP) was significantly increased (P<0.05) in the OVX rat (174+/-8 mmHg), as compared to sham (135+/-6 mmHg). The resting tension of isolated cerebral arteries from OVX rats (186+/-15 mg) was significantly elevated (P<0.05), as compared to sham (129+/-9 mg). Phenylephrine treatment did not elicit a constriction of cerebral arteries isolated from sham rats, whereas a potent response (P<0.05) was observed in OVX rats. Nitric oxide (NO) synthase inhibition with L-NNA led to a limited contraction in sham rats (8+/-3% of Emax), whereas a significant (P<0.05) increase was observed in OVX rats (34+/-12% of Emax). Lastly, vascular sensitivity (pD2) to sodium nitroprusside was significantly increased (P<0.05) in OVX rats, as compared to sham. 4. Tamoxifen therapy normalized the resting tension of isolated cerebral arteries from OVX rats, abrogated phenylephrine-mediated contraction, and modestly reduced SAP. By contrast, tamoxifen treatment of OVX rats did not attenuate L-NNA-mediated contractile response of cerebral arteries. 5. These data demonstrate that the cerebral artery

  9. Vitamins as influenza vaccine adjuvant components.

    PubMed

    Quintilio, Wagner; de Freitas, Fábio Alessandro; Rodriguez, Dunia; Kubrusly, Flavia Saldanha; Yourtov, Dimitri; Miyaki, Cosue; de Cerqueira Leite, Luciana Cezar; Raw, Isaias

    2016-10-01

    A number of adjuvant formulations were assayed in mice immunized with 3.75 µg of A/California/7/2009 (H1N1) pdm09 influenza vaccine with vitamins A, D and/or E in emulsions or B2 and/or B9 combined with Bordetella pertussis MPLA and/or alum as adjuvants. Squalene was used as positive control, as well as MPLA with alum. The immune response was evaluated by a panel of tests, including a hemagglutination inhibition (HAI) test, ELISA for IgG, IgG1, and IgG2a and IFN-γ, IL-2, IL-6 and IL-10 quantification in splenocyte culture supernatant after stimulus with influenza antigen. Immunological memory was evaluated using a 1/10 dose booster 60 days after the first immunization followed by assessment of the response by HAI, IgG ELISA, and determination of the antibody affinity index. The highest increases in HAI, IgG1 and IgG2a titers were obtained with the adjuvant combinations containing vitamin E, or the hydrophilic combinations containing MPLA and alum or B2 and alum. The IgG1/IgG2a ratio indicates that the response to the combination of B2 with alum would have more Th2 character than the combination of MPLA with alum. In an assay to investigate the memory response, a significant increase in HAI titer was observed with a booster vaccine dose at 60 days after immunization with vaccines containing MPLA with alum or B2 with alum. Overall, of the 27 adjuvant combinations, MPLA with alum and B2 with alum were the most promising adjuvants to be evaluated in humans. PMID:27449155

  10. Vitamins as influenza vaccine adjuvant components.

    PubMed

    Quintilio, Wagner; de Freitas, Fábio Alessandro; Rodriguez, Dunia; Kubrusly, Flavia Saldanha; Yourtov, Dimitri; Miyaki, Cosue; de Cerqueira Leite, Luciana Cezar; Raw, Isaias

    2016-10-01

    A number of adjuvant formulations were assayed in mice immunized with 3.75 µg of A/California/7/2009 (H1N1) pdm09 influenza vaccine with vitamins A, D and/or E in emulsions or B2 and/or B9 combined with Bordetella pertussis MPLA and/or alum as adjuvants. Squalene was used as positive control, as well as MPLA with alum. The immune response was evaluated by a panel of tests, including a hemagglutination inhibition (HAI) test, ELISA for IgG, IgG1, and IgG2a and IFN-γ, IL-2, IL-6 and IL-10 quantification in splenocyte culture supernatant after stimulus with influenza antigen. Immunological memory was evaluated using a 1/10 dose booster 60 days after the first immunization followed by assessment of the response by HAI, IgG ELISA, and determination of the antibody affinity index. The highest increases in HAI, IgG1 and IgG2a titers were obtained with the adjuvant combinations containing vitamin E, or the hydrophilic combinations containing MPLA and alum or B2 and alum. The IgG1/IgG2a ratio indicates that the response to the combination of B2 with alum would have more Th2 character than the combination of MPLA with alum. In an assay to investigate the memory response, a significant increase in HAI titer was observed with a booster vaccine dose at 60 days after immunization with vaccines containing MPLA with alum or B2 with alum. Overall, of the 27 adjuvant combinations, MPLA with alum and B2 with alum were the most promising adjuvants to be evaluated in humans.

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

    SciTech Connect

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

    2015-08-28

    Tamoxifen is a selective estrogen receptor (ER) modulator which is widely used to generate inducible conditional transgenic mouse models. Activation of ER signaling plays an important role in the regulation of adipose tissue (AT) metabolism. We therefore tested the hypothesis that tamoxifen administration causes changes in AT biology in vivo. 12 weeks old male C57BL/6NTac mice were treated with either tamoxifen (n = 18) or vehicle (n = 18) for 5 consecutive days. Tamoxifen treatment effects on body composition, energy homeostasis, parameters of AT biology, glucose and lipid metabolism were investigated up to an age of 18 weeks. We found that tamoxifen treatment causes: I) significantly increased 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.

  12. Identifying predictive clinical characteristics of the treatment efficacy of mirtazapine monotherapy for major depressive disorder

    PubMed Central

    Tsutsumi, Takahiro; Sugawara, Hiroko; Ito, Ryoko; Asano, Mizuho; Shimizu, Satoru; Ishigooka, Jun; Nishimura, Katsuji

    2016-01-01

    Background Mirtazapine, which is classified as a noradrenergic and specific serotonergic antidepressant, is widely prescribed for the treatment of major depressive disorder. The potential predictive factors of the efficacy of mirtazapine and the tolerability based on the incidence of oversedation and jitteriness/anxiety syndrome were evaluated. Patients and methods Patients with major depressive disorder were retrospectively investigated. Study subjects comprised 68 patients with depression who received mirtazapine as an initial antidepressant at the Department of Psychiatry of the Tokyo Women’s Medical University Hospital from September 2009 to March 2013. The efficacy of mirtazapine monotherapy was evaluated based on the Clinical Global Impression Improvement score. Clinical characteristics were compared between remission and nonremission groups to determine the factors predicting the efficacy. Moreover, discontinuation rates due to adverse effects, including oversedation and jitteriness/anxiety syndrome, were examined, and the effects of confounding factors were evaluated. Results The remission rate of mirtazapine monotherapy was 36.8% among the 68 enrolled subjects. The mean final doses in the remission and nonremission groups were 27.6±13.5 mg and 26.0±14.1 mg, respectively, and there was no significant difference between them. Multiple logistic analyses revealed that the absence of guilt (odds ratio [OR] =0.15; 95% CI [1.66–37.24], P=0.006) and the presence of psychomotor retardation (OR =4.30; 95% CI [1.30–16.60], P=0.016) were significantly related to the efficacy of mirtazapine monotherapy. The discontinuation rates due to oversedation and jitteriness/anxiety syndrome were 13.2% and 11.8%, respectively. Age did not differ significantly between patients with or without oversedation or jitteriness/anxiety syndrome (P=0.078 and P=0.579, respectively). Conclusion The absence of guilt and the presence of psychomotor retardation may predict the efficacy

  13. Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis

    PubMed Central

    Fleischmann, Roy M; Huizinga, Tom W J; Kavanaugh, Arthur F; Wilkinson, Bethanie; Kwok, Kenneth; DeMasi, Ryan; van Vollenhoven, Ronald F

    2016-01-01

    Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib monotherapy was previously shown to inhibit structural damage, reduce clinical signs and symptoms of RA, and improve physical functioning over 24 months in methotrexate (MTX)-naive adult patients with RA. In this post hoc analysis, we compared efficacy and safety of tofacitinib in patients with early (disease duration <1 year) versus established (≥1 year) RA. Methods MTX-naive patients ≥18 years with active RA received tofacitinib monotherapy (5 or 10 mg two times a day, or MTX monotherapy, in a 24-month Phase 3 trial. Results Of 956 patients (tofacitinib 5 mg two times a day, n=373; tofacitinib 10 mg two times a day, n=397; MTX, n=186), 54% had early RA. Baseline disease activity and functional disability were similar in both groups; radiographic damage was greater in patients with established RA. At month 24, clinical response rates were significantly greater in patients with early versus established RA in the tofacitinib 5 mg two times a day group. Both tofacitinib doses had greater effects on clinical, functional and radiographic improvements at 1 and 2 years compared with MTX, independent of disease duration. No new safety signals were observed. Conclusions Treatment response was generally similar in early and established RA; significantly greater improvements were observed at month 24 with tofacitinib 5 mg two times a day in early versus established RA. Tofacitinib 5 and 10 mg two times a day demonstrated greater efficacy versus MTX irrespective of disease duration. No difference in safety profiles was observed between patients with early or established RA. Trial registration number NCT01039688; Results. PMID:27493790

  14. Alemtuzumab induction with tacrolimus monotherapy in 25 pediatric renal transplant recipients.

    PubMed

    Sung, Jennifer; Barry, John M; Jenkins, Randy; Rozansky, David; Iragorri, Sandra; Conlin, Michael; Al-Uzri, Amira

    2013-12-01

    ALA induction in transplantation has been shown to reduce the need for maintenance immunosuppression. We report the outcome of 25 pediatric renal transplants between 2007 and 2010 using ALA induction followed by tacrolimus maintenance monotherapy. Patient ages were 1-19 yr (mean 14 ± 4.1 yr). Time of follow-up was 7-51 months (mean 26 ± 13 months). Tacrolimus monotherapy was maintained in 48% of patients, and glucocorticoids were avoided in 80% of recipients. Mean plasma creatinine and GFR at one yr post-transplant were 0.88 ± 0.3 mg/dL and 104.4 ± 25 mL/min/1.73m(2) , respectively. One, two, and three-yr actuarial patient and graft survival rates were 100%. The incidence of early AR (<12 months after transplantation) was 12%, while the incidence of late AR (after 12 months) was 16%. Forty-four percent of the recipients recovered normal, baseline renal function after an episode of AR, and 44% had persistent renal dysfunction (plasma creatinine 1.0-1.8 mg/dL). One graft was lost four yr after transplantation due to medication non-compliance. Four (16%) patients developed BK or CMV infection. In our experience, ALA induction with tacrolimus monotherapy resulted in excellent short- and mid-term patient and graft survival in low-immunologic risk pediatric renal transplant recipients.

  15. Prostate-Specific Antigen Bounce After High-Dose-Rate Monotherapy for Prostate Cancer

    SciTech Connect

    Mehta, Niraj H.; Kamrava, Mitchell; Wang, Pin-Chieh; Steinberg, Michael; Demanes, Jeffrey

    2013-07-15

    Purpose: To characterize the magnitude and kinetics of prostate-specific antigen (PSA) bounces after high-dose-rate (HDR) monotherapy and determine relationships between certain clinical factors and PSA bounce. Methods and Materials: Longitudinal PSA data and various clinical parameters were examined in 157 consecutive patients treated with HDR monotherapy between 1996 and 2005. We used the following definition for PSA bounce: rise in PSA ≥threshold, after which it returns to the prior level or lower. Prostate-specific antigen failure was defined per the Phoenix definition (nadir +2 ng/mL). Results: A PSA bounce was noted in 67 patients (43%). The number of bounces per patient was 1 in 45 cases (67%), 2 in 19 (28%), 3 in 2 (3%), 4 in 0, and 5 in 1 (1%). The median time to maximum PSA bounce was 1.3 years, its median magnitude was 0.7, and its median duration was 0.75 years. Three patients (2%) were noted to have PSA failure. None of the 3 patients who experienced biochemical failure exhibited PSA bounce. In the fully adjusted model for predicting each bounce, patients aged <55 years had a statistically significant higher likelihood of experiencing a bounce (odds ratio 2.22, 95% confidence interval 1.38-3.57, P=.001). There was also a statistically significant higher probability of experiencing a bounce for every unit decrease in Gleason score (odds ratio 1.52, 95% confidence interval 1.01-2.04, P=.045). Conclusions: A PSA bounce occurs in a significant percentage of patients treated with HDR monotherapy, with magnitudes varying from <1 in 28% of cases to ≥1 in 15%. The median duration of bounce is <1 year. More bounces were identified in patients with lower Gleason score and age <55 years. Further investigation using a model to correlate magnitude and frequency of bounces with clinical variables are under way.

  16. Long-term assessment of prostaglandin analogs and timolol fixed combinations vs prostaglandin analogs monotherapy

    PubMed Central

    Liu, Ai-Wei; Gan, Lin-Yang; Yao, Xiang; Zhou, Jian

    2016-01-01

    AIM To draw a Meta-analysis over the comparison of the intraocular pressure (IOP)-lowering efficacy and safety between the commonly used fixed-combinations of prostaglandin analogs and 0.5% timolol with prostaglandin analogs (PGAs) monotherapy. METHODS After searching the published reports from MEDLINE, EMBASE, the Cochrane Library, all randomized controlled clinical trials (RCTs) comparing the fixed combination of PGAs/timolol therapy (FCs) and PGAs monotherapy with treatment duration at least 6mo were included. The efficacy outcomes were mean diurnal IOP, percentage of participants whose IOP were lower than 18 mm Hg, incidence of visual field change, while the safety outcomes included corneal side effects, hyperemia and eye irritation. The analysis was carried out in RevMan version 5.3 software. RESULTS After six-month medical intervention, the mean diurnal IOP of FCs was lower than PGAs (MD -1.14, 95% CI -1.82 to -0.46, P=0.001); the percentage of target IOP achieving between FCs and PGAs showed no significant difference (RR 1.18, 95% CI 0.97 to 1.43, P=0.10). No statistically significant differences of the incidence of hyperemia (RR 0.67, 95% CI 0.45 to 1.01, P=0.06) and eye irritation (RR 1.20, 95% CI 0.95 to 1.51, P=0.12) between the FCs and PGAs monotherapy were detected. Only one research involved in corneal events, result of this trial revealed no difference between two intervention groups regarding corneal effects (central endothelial cell density, MD -0.20, 95% CI -0.72 to 0.32, P=0.45; central corneal thickness, MD -0.01, 95% CI -0.02 to 0.00, P=0.23). The evaluation of visual field change was not performed due to the limited duration of the trials included in this Meta-analysis. CONCLUSION The long-term efficacy of the FCs overweighed the PGAs monotherapy in lowering IOP, but in the incidence of hyperemia and eye irritation syndromes, the differences are not statically significant. More RCTs with detailed and authentic data over the assessments of

  17. Sustainable Efficacy of Switching From Intravenous to Subcutaneous Tocilizumab Monotherapy in Patients With Rheumatoid Arthritis

    PubMed Central

    Atsumi, Tatsuya; Fukuda, Takaaki; Hirabayashi, Yasuhiko; Inaba, Masaaki; Ishiguro, Naoki; Kai, Motokazu; Kawabata, Daisuke; Kida, Daihei; Kohsaka, Hitoshi; Matsumura, Ryutaro; Minota, Seiji; Mukai, Masaya; Sumida, Takayuki; Takasugi, Kiyoshi; Tamaki, Shigenori; Takeuchi, Tsutomu; Ueda, Atsuhisa; Yamamoto, Kazuhiko; Yamanaka, Hisashi; Yoshifuji, Hajime; Nomura, Akira

    2015-01-01

    Objective To evaluate the efficacy and safety of switching from intravenous (IV) tocilizumab (TCZ) to subcutaneous (SC) TCZ monotherapy in rheumatoid arthritis patients. Methods Patients who had completed 24 weeks of TCZ‐SC (162 mg/2 weeks) or TCZ‐IV (8 mg/kg/4 weeks) monotherapy in the double‐blind period of the MUSASHI study were enrolled in an 84‐week open‐label extension period. All received TCZ‐SC (162 mg/2 weeks) monotherapy. Effects of the IV to SC switch were evaluated at week 36 (12 weeks after switching). Results Overall, 319 patients received ≥1 dose of TCZ‐SC during the open‐label extension period; 160 switched from TCZ‐IV to TCZ‐SC (TCZ IV/SC) and 159 continued TCZ‐SC (TCZ SC/SC). Disease Activity Score in 28 joints using the erythrocyte sedimentation rate clinical remission rates were 62.5% (100 of 160) for TCZ IV/SC and 50.0% (79 of 158) for TCZ SC/SC at week 24, and were maintained at 62.5% (100 of 160) and 57.0% (90 of 158), respectively, at week 36. In the TCZ IV/SC group, 9% of patients (9 of 100) who had achieved remission at week 24 could not maintain remission at week 36. In TCZ IV/SC patients weighing ≥70 kg, the percentage with a sufficient serum TCZ concentration (≥1 μg/ml) decreased from 90.9% (10 of 11) at week 24 to 45.5% (5 of 11) at week 36. Overall safety profiles were similar in TCZ IV/SC and TCZ SC/SC except for mild injection site reactions in TCZ IV/SC. Conclusion Efficacy is adequately maintained in most patients switching from TCZ‐IV (8 mg/kg/4 weeks) to TCZ‐SC (162 mg/2 weeks) monotherapy. Patients receiving TCZ‐IV can switch to TCZ‐SC without serious safety concerns. Clinical efficacy may be reduced after switching in some patients with high body weight. PMID:25832859

  18. Hepatitis B Virus Reactivation Following Salazosulfapyridine Monotherapy in a Patient with Rheumatoid Arthritis.

    PubMed

    Akashi, Kengo; Saegusa, Jun; Nakamachi, Yuji; Nakazawa, Takashi; Kumagai, Shunichi; Morinobu, Akio

    2016-01-01

    A 72-year-old man was diagnosed with rheumatoid arthritis (RA) and prior hepatitis B virus (HBV) infection. He began treatment with salazosulfapyridine (SASP). Several months later, his blood tests reflected a slightly elevated liver function. Serum tests were positive for hepatitis B surface antigen and HBV-DNA, and the diagnosis of de novo HBV hepatitis was made. A genetic analysis showed that he had polymorphisms of ABCG2 and NAT2, which could lead to high plasma concentrations of SASP and sulfapyridine. To the best of our knowledge, this is the first report of de novo hepatitis developing during SASP monotherapy for RA. PMID:27181550

  19. 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.

    PubMed

    Silva, F B; Romero, W G; Carvalho, A L R; Borgo, M V; Amorim, M H C; Gouvea, S A; Abreu, G R

    2015-02-01

    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.

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

    PubMed

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

    2015-08-28

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

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

    PubMed

    O'Hagan, Derek T; Fox, Christopher B

    2015-06-01

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

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

    PubMed

    O'Hagan, Derek T; Fox, Christopher B

    2015-06-01

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

  3. Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98

    PubMed Central

    Thuerlimann, Beat

    2007-01-01

    The BIG 1-98 trial is a large, randomized, independently conducted clinical trial designed to compare the efficacy of upfront letrozole versus tamoxifen monotherapy and to compare sequential or up-front use of letrozole and/or tamoxifen as an early adjuvant therapy for patients with early breast cancer. We report on the results from the primary core analysis of the BIG 1-98 trial of 8,010 patients, which compares monotherapy with letrozole versus tamoxifen. This pre-planned core analysis allowed the use of patient data from the monotherapy arms of letrozole and tamoxifen and from the sequential arms prior to the drug switch point. Patients randomized to letrozole had a 19% improved disease-free survival (hazard ratio [HR] = 0.81; P = 0.003), due especially to reduced distant metastases (HR = 0.73; P = 0.001). A 14% risk reduction of fatal events in favor of letrozole was also observed (P = NS). The results from the monotherapy arms alone confirmed the findings from the primary core analysis. Based on the results from this trial, the aromatase inhibitor letrozole (Femara®) is currently recommended as a part of standard adjuvant therapy for postmenopausal women with endocrine-responsive breast cancer and has recently been approved in the early adjuvant setting in both Europe and the United States. A subsequent analysis after additional follow-up will address the question of monotherapy versus sequential therapy. PMID:17912636

  4. Effect of Tamoxifen and Lithium on Treatment of Acute Mania Symptoms in Children and Adolescents

    PubMed Central

    Fallah, Elham; Arman, Sorror; Najafi, Mostafa; Shayegh, Bahar

    2016-01-01

    Objective Many studies have supported the role of protein kinase C (PKC) inhibitors in the physiopathology and treatment of bipolar disorder in adults. Tamoxifen is one of the drugs with the effect of PKC inhibition. This study aimed to determine the effect of tamoxifen on the rate of improvement mania symptoms in the sample of children and adolescents with acute mania. Materials & Methods In this randomized, placebo-controlled clinical trial study, registered in www.irct.ir with the code of IRCT201410126418N3, overall 44 patients with bipolar disorder with acute manic episode were randomly assigned into treatment and control groups. The serum levels of lithium and tamoxifen among the participants in the treatment groups were 0.8 -1.1 mg and 20-40 mg per day respectively. Serum level of lithium among participants in the control group was similar. The main comparisons were made based on the Young Mania Rating Scale (YMRS) and Children Depression Inventory (CDI) scores of the participants at baseline and at the end of each study week. The pharmacological side effects of serum level of lithium were examined weekly. Analysis of Covariance(ANCOVA) test was used for the statistical analysis. Results There was no difference in the baseline score of YMRS and CDI in the treatment and control groups while a statistical significant difference (P < 0.05) in these scores was found between and within the groups. Conclusion The addition of tamoxifen to lithium causes a significant difference in reducing the symptoms of mania and depression in the treatment group compared to the control group. PMID:27247580

  5. Stimulation of calcitonin secretory capacity by increased serum levels of testosterone in men treated with tamoxifen.

    PubMed

    Schopman, W; Slager, E; Hackeng, W H; Mulder, H

    1987-12-01

    Previous studies have suggested that sex steroids, including both oestrogen and testosterone, influence calcitonin secretion. However, a negative effect of gonadotrophins on calcitonin has not been excluded. Twelve men with infertility and low-normal serum levels of testosterone were studied before and during tamoxifen therapy. Increases in the serum levels of LH, FSH, testosterone and calcitonin were observed after treatment. Our findings suggest that testosterone has a direct influence on calcitonin secretion. PMID:3123401

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

    PubMed Central

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

    2016-01-01

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

  7. Quantitative analysis of hindlimbs locomotion kinematics in spinalized rats treated with Tamoxifen plus treadmill exercise.

    PubMed

    Osuna-Carrasco, L P; López-Ruiz, J R; Mendizabal-Ruiz, E G; De la Torre-Valdovinos, B; Bañuelos-Pineda, J; Jiménez-Estrada, I; Dueñas-Jiménez, S H

    2016-10-01

    Locomotion recovery after a spinal cord injury (SCI) includes axon regeneration, myelin preservation and increased plasticity in propriospinal and descending spinal circuitries. The combined effects of tamoxifen and exercise after a SCI were analyzed in this study to determine whether the combination of both treatments induces the best outcome in locomotion recovery. In this study, the penetrating injury was provoked by a sharp projectile that penetrates through right dorsal and ventral portions of the T13-L1 spinal segments, affecting propriospinal and descending/ascending tracts. Intraperitoneal application of Tamoxifen and a treadmill exercise protocol, as rehabilitation therapies, separately or combined, were used. To evaluate the functional recovery, angular patterns of the hip, knee and ankle joints as well as the leg pendulum-like movement (PLM) were measured during the unrestricted gait of treated and untreated (UT) animals, previously and after the traumatic injury (15 and 30days post-injury (dpi)). A pattern (curve) comparison analysis was made by using a locally designed Matlab script that determines the Frechet dissimilarity. The SCI magnitude was assessed by qualitative and quantitative histological analysis of the injury site 30days after SCI. Our results showed that all treated groups had an improvement in hindlimbs kinematics compared to the UT group, which showed a poor gait locomotion recovery throughout the rehabilitation period. The group with the combined treatment (tamoxifen+exercise (TE)) presented the best outcome. In conclusion, tamoxifen and treadmill exercise treatments are complementary therapies for the functional recovery of gait locomotion in hemi-spinalized rats. PMID:27450566

  8. Modeling Murine Gastric Metaplasia Through Tamoxifen-Induced Acute Parietal Cell Loss.

    PubMed

    Saenz, Jose B; Burclaff, Joseph; Mills, Jason C

    2016-01-01

    Parietal cell loss represents the initial step in the sequential progression toward gastric adenocarcinoma. In the setting of chronic inflammation, the expansion of the mucosal response to parietal cell loss characterizes a crucial transition en route to gastric dysplasia. Here, we detail methods for using the selective estrogen receptor modulator tamoxifen as a novel tool to rapidly and reversibly induce parietal cell loss in mice in order to study the mechanisms that underlie these pre-neoplastic events. PMID:27246044

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

    PubMed Central

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

    2015-01-01

    Spinal cord injury (SCI) is a devastating condition that produces significant changes in the lifestyle of patients. Many molecular and cellular events are triggered after the initial physical impact to the cord. Two major phases have been described in the field of SCI: an acute phase and late phase. Most of the therapeutic strategies are focused on the late phase because this provides an opportunity to target cellular events like apoptosis, demyelination, scar formation and axonal outgrowth. In this mini-review, we will focus on two agents (tamoxifen and a Src kinase family inhibitor known as PP2) that have been shown in our laboratory to produce neuroprotective (increase cell survival) and/or regenerative (axonal outgrowth) actions. The animal model used in our laboratory is adult female rat (~250 g) with a moderate contusion (12.5 mm) to the spinal cord at the T10 level, using the MASCIS impactor device. Tamoxifen or PP2 was administered by implantation of a 15 mg pellet (Innovative Research of America, Sarasota, FL, USA) or by intraperitoneal injections (1.5 mg/kg, every 3 days), respectively, to produce a long-term effect (28 days). Tamoxifen and the Src kinase inhibitor, PP2, are drugs that in rats with a moderate spinal cord injury promote functional locomotor recovery, increase spared white matter tissue, and stimulate axonal outgrowth. Moreover, tamoxifen reduces the formation of reactive oxygen species. Therefore, these drugs are possible therapeutic agents that have a neuroprotective/regenerative activity in vertebrates with SCI. PMID:25878585

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

    PubMed

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

    2015-03-01

    Spinal cord injury (SCI) is a devastating condition that produces significant changes in the lifestyle of patients. Many molecular and cellular events are triggered after the initial physical impact to the cord. Two major phases have been described in the field of SCI: an acute phase and late phase. Most of the therapeutic strategies are focused on the late phase because this provides an opportunity to target cellular events like apoptosis, demyelination, scar formation and axonal outgrowth. In this mini-review, we will focus on two agents (tamoxifen and a Src kinase family inhibitor known as PP2) that have been shown in our laboratory to produce neuroprotective (increase cell survival) and/or regenerative (axonal outgrowth) actions. The animal model used in our laboratory is adult female rat (~250 g) with a moderate contusion (12.5 mm) to the spinal cord at the T10 level, using the MASCIS impactor device. Tamoxifen or PP2 was administered by implantation of a 15 mg pellet (Innovative Research of America, Sarasota, FL, USA) or by intraperitoneal injections (1.5 mg/kg, every 3 days), respectively, to produce a long-term effect (28 days). Tamoxifen and the Src kinase inhibitor, PP2, are drugs that in rats with a moderate spinal cord injury promote functional locomotor recovery, increase spared white matter tissue, and stimulate axonal outgrowth. Moreover, tamoxifen reduces the formation of reactive oxygen species. Therefore, these drugs are possible therapeutic agents that have a neuroprotective/regenerative activity in vertebrates with SCI. PMID:25878585

  11. High-density array analysis of DNA methylation in Tamoxifen-resistant breast cancer cell lines.

    PubMed

    Williams, Kristin E; Anderton, Douglas L; Lee, Maxwell P; Pentecost, Brian T; Arcaro, Kathleen F

    2014-02-01

    Roughly two-thirds of all breast cancers are ERα-positive and can be treated with the antiestrogen, Tamoxifen, however resistance occurs in 33% of women who take the drug for more than 5 y. Aberrant DNA methylation, an epigenetic mechanism that alters gene expression in cancer, is thought to play a role in this resistance. To develop an understanding of Tamoxifen-resistance and identify novel pathways and targets of aberrant methylation, DNA from MCF-7 breast cancer cells and Tamoxifen-resistant derivatives, TMX2-11 and TMX2-28, were analyzed using the Illumina HumanMethylation450 BeadChip. Normalizing against MCF-7 values, ERα-positive TMX2-11 had 4000 hypermethylated sites and ERα-negative TMX2-28 had over 33 000. Analysis of CpG sites altered in both TMX2-11 and TMX2-28 revealed that the Tamoxifen-resistant cell lines share 3000 hypermethylated and 200 hypomethylated CpGs. ZNF350 and MAGED1, two genes hypermethylated in both cell lines, were examined in greater detail. Treatment with 5-aza-2ꞌdeoxycitidine caused a significant reduction in promoter methylation of both ZNF350 and MAGED1 and a corresponding increase in expression in TMX2-28. A similar relationship between methylation and expression was not detected in TMX2-11. Our findings are indicative of the variable responses to methylation-targeted breast cancer therapy and highlight the need for biomarkers that accurately predict treatment outcome.

  12. A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas.

    PubMed

    Odia, Yazmín; Kreisl, Teri N; Aregawi, Dawit; Innis, Ellen K; Fine, Howard A

    2015-10-01

    NF-kB inhibition by bortezomib enhances tamoxifen-induced apoptosis in preclinical glioma models. We conducted a single institution, phase II trial to evaluate efficacy and safety of high dose tamoxifen with bortezomib in adults with recurrent malignant gliomas. The primary endpoint was radiographic response. Concurrent enzyme inducing anticonvulsants and grade ≥2 peripheral neuropathy were exclusion criteria. Patients received tamoxifen (120 mg PO twice daily) and bortezomib (1.3 mg/m2 IV on days 3, 6, 10, 13, 24, 27, 31, and 34) per 6-week cycles. We enrolled 42 patients with anaplastic gliomas (AGs, n = 12) and glioblastomas (GBMs, n = 30), 32 males and 10 females. Median age was 38 years (range 22-65) and 48 years (range 19-68) for AGs and GBMs, respectively. median karnofsky performance status was 90% (range 70-100) for AGs and 80% (range 60-100) for GBMs. Median prior therapies was 3, ranging 1-7. Grade ≥3 toxicities included lymphopenia (4/42), hypophosphatemia (3/42), thromobocytopenia (2/42), and 1/42 with hyponatremia, headache, dyspnea, or DVT. One patient withdrew consent, two were removed for toxicity, and all others discontinued for progression. Among 40 patients evaluable for response, only one achieved stable disease for 3 months; all others progressed rapidly. For AGs and GBMs respectively, median progression-free survival was 5.9 and 5.7 weeks and median overall survival was 25.6 and 14.7 weeks. The study was closed due to poor accrual and therapeutic futility. Combination tamoxifen and bortezomib has no activity in recurrent malignant gliomas. Poor penetration across blood brain barrier of bortezomib likely limited efficacy.

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

    PubMed

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

    2016-09-01

    Conjugation of antitumor drug tamoxifen and its metabolites, 4-hydroxytamxifen and ednoxifen with synthetic polymers poly(ethylene glycol) (PEG), methoxypoly (ethylene glycol) polyamidoamine (mPEG-PAMAM-G3) and polyamidoamine (PAMAM-G4) dendrimers was studied in aqueous solution at pH 7.4. Multiple spectroscopic methods, transmission electron microscopy (TEM) and molecular modeling were used to characterize the drug binding process to synthetic polymers. Structural analysis showed that drug-polymer binding occurs via both H-bonding and hydrophobic contacts. The order of binding is PAMAM-G4>mPEG-PAMAM-G3>PEG-6000 with 4-hydroxttamoxifen forming more stable conjugate than tamoxifen and endoxifen. Transmission electron microscopy showed significant changes in carrier morphology with major changes in the shape of the polymer aggregate as drug encapsulation occurred. Modeling also showed that drug is located in the surface and in the internal cavities of PAMAM with the free binding energy of -3.79 for tamoxifen, -3.70 for 4-hydroxytamoxifen and -3.69kcal/mol for endoxifen, indicating of spontaneous drug-polymer interaction at room temperature. PMID:27137803

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2016-01-14

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

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

    PubMed

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

    2016-01-14

    Almost 70% of breast cancers are estrogen receptor α (ERα) positive. Tamoxifen, a selective estrogen receptor modulator (SERM), represents the standard of care for many patients; however, 30-50% develop resistance, underlining the need for alternative therapeutics. Paradoxically, agonists at ERα such as estradiol (E2) have demonstrated clinical efficacy in patients with heavily treated breast cancer, although side effects in gynecological tissues are unacceptable. A drug that selectively mimics the actions of E2 in breast cancer therapy but minimizes estrogenic effects in other tissues is a novel, therapeutic alternative. We hypothesized that a selective human estrogen receptor partial agonist (ShERPA) at ERα would provide such an agent. Novel benzothiophene derivatives with nanomolar potency in breast cancer cell cultures were designed. Several showed partial agonist activity, with potency of 0.8-76 nM, mimicking E2 in inhibiting growth of tamoxifen-resistant breast cancer cell lines. Three ShERPAs were tested and validated in xenograft models of endocrine-independent and tamoxifen-resistant breast cancer, and in contrast to E2, ShERPAs did not cause significant uterine growth. PMID:26681208

  18. Troglitazone enhances tamoxifen-induced growth inhibitory activity of MCF-7 cells

    SciTech Connect

    Yu, Hong-Nu; Noh, Eun-Mi; Lee, Young-Rae; Roh, Si-Gyun; Song, Eun-Kyung; Han, Myung-Kwan; Lee, Yong-Chul; Shim, In Kyong; Lee, Seung Jin; Jung, Sung Hoo; Kim, Jong-Suk Youn, Hyun Jo

    2008-12-05

    Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligands have been identified as a potential source of therapy for human cancers. However, PPAR{gamma} ligands have a limitation for breast cancer therapy, since estrogen receptor {alpha} (ER{sub {alpha}}) negatively interferes with PPAR{gamma} signaling in breast cancer cells. Here we show that ER{sub {alpha}} inhihits PPAR{gamma} transactivity and ER{sub {alpha}}-mediated inhibition of PPAR{gamma} transactivity is blocked by tamoxifen, an estrogen receptor blocker. The activation of ER{sub {alpha}} with 17-{beta}-estradiol blocked PPRE transactivity induced by troglitazone, a PPAR{gamma} ligand, indicating the resistance of ER{sub {alpha}}-positive breast cancer cells to troglitazone. Indeed, troglitazone inhibited the growth of ER{sub {alpha}}-negative MDA-MB-231 cells more than that of ER{sub {alpha}}-positive MCF-7 cells. Combination of troglitazone with tamoxifen led to a marked increase in growth inhibition of ER{sub {alpha}}-positive MCF-7 cells compared to either agent alone. Our data indicates that troglitazone enhances the growth inhibitory activity of tamoxifen in ER{sub {alpha}}-positive MCF-7 cells.

  19. Tamoxifen prevents apoptosis and follicle loss from cyclophosphamide in cultured rat ovaries.

    PubMed

    Piasecka-Srader, Joanna; Blanco, Fernando F; Delman, Devora H; Dixon, Dan A; Geiser, James L; Ciereszko, Renata E; Petroff, Brian K

    2015-05-01

    Recent studies documented that the selective estrogen receptor modulator tamoxifen prevents follicle loss and promotes fertility following in vivo exposure of rodents to irradiation or ovotoxic cancer drugs, cyclophosphamide and doxorubicin. In an effort to characterize the ovarian-sparing mechanisms of tamoxifen in preantral follicle classes, cultured neonatal rat ovaries (Day 4, Sprague Dawley) were treated for 1-7 days with active metabolites of cyclophosphamide (i.e., 4-hydroxycyclophosphamide; CTX) (0, 1, and 10 μM) and tamoxifen (i.e., 4-hydroxytamoxifen; TAM) (0 and 10 μM) in vitro, and both apoptosis and follicle numbers were measured. CTX caused marked follicular apoptosis and follicular loss. TAM treatment decreased follicular loss and apoptosis from CTX in vitro. TAM alone had no effect on these parameters. IGF-1 and IGF-1 receptor were assessed in ovarian tissue showing no impact of TAM or CTX on these endpoints. Targeted mRNA analysis during follicular rescue by TAM revealed decreased expression of multiple genes related to inflammation, including mediators of lipoxygenase and prostaglandin production and signaling (Alox5, Pla2g1b, Ptgfr), cytokine binding (Il1r1, Il2rg ), apoptosis (Tnfrsf1a), second messenger signaling (Mapk1, Mapk14, Plcg1), as well as tissue remodeling and vasodilation (Bdkrb2, Klk15). The results suggest that TAM protects the ovary from CTX-mediated toxicity through direct ovarian actions that oppose follicular loss. PMID:25833159

  20. Presumed Allergic Proctocolitis Resolves with Probiotic Monotherapy: A Report of 4 Cases

    PubMed Central

    Martin, Victoria J.; Shreffler, Wayne G.; Yuan, Qian

    2016-01-01

    Case series Patients: — Final Diagnosis: Allergic proctocolitis Symptoms: Hematochezia • fussiness Medication: — Clinical Procedure: — Specialty: Pediatrics and Neonatology Objective: Unusual clinical course Background: The prevalence of allergic diseases has been dramatically rising in the United States and other developed nations over recent decades. Growing evidence suggests a partial role for the microbiome in the development of these allergic diseases. Food protein-induced allergic proctocolitis (AP) (also referred to as cow’s milk protein intolerance or allergy) is among the earliest and most common food allergic diseases of infancy, yet its patho physiology is not well understood. The currently accepted clinical practice is to restrict the diet until 12 months of age. Case Reports: We present 4 cases of clinically diagnosed AP whose symptoms quickly and completely resolved with probiotic Lactobacillus rhamnosus GG (LGG) monotherapy. All 4 infants avoided any dietary restrictions. The range of time from probiotic initiation to symptom resolution was 7–28 days. Conclusions: These cases suggest an important role for the infant intestinal microbiome in the development of gastrointestinal mucosal food allergies such as AP. Prospective investigation of the intestinal microbiome in infants with AP may further our understanding of this disease’s pathogenesis. The potential use of probiotic monotherapy in the treatment of AP also warrants further investigation. PMID:27568925

  1. Efficacy and Safety of Levetiracetam and Carbamazepine as Monotherapy in Partial Seizures

    PubMed Central

    Suresh, Swaroop Hassan; Chakraborty, Ananya; Virupakshaiah, Akash; Kumar, Nithin

    2015-01-01

    Introduction. Levetiracetam (LEV) is a newer antiepileptic drug with better pharmacokinetic profile. Currently, it is frequently used for the treatment of partial seizures. The present study was undertaken to compare the efficacy and safety of LEV and Carbamazepine (CBZ) in partial epilepsy. Methods. This was a prospective, open labeled, randomized study. It was conducted in participants suffering from partial seizures after the approval of ethics committee and written informed consent. The first group received Tab LEV (500 to 3000 mg/day) and the second group received Tab CBZ (300 to 600 mg/day). The primary outcomes were efficacy and safety. The secondary outcome was the Quality of Life (QOL). Efficacy was assessed by comparing the seizure freedom rates at the end of 6 months. Safety profile was evaluated by comparing the adverse effects. QOL was assessed by QOLIE-10 scale. Results. The overall seizure freedom rate at the end of 6 months was 71.42% in CBZ group compared to 78.57% in LEV group (p = 0.2529). Both LEV and CBZ reported a similar incidence of adverse reactions. LEV group reported more behavioral changes like increased aggression and anxiety. Also, it showed better QOL compared to the CBZ group. Conclusion. LEV monotherapy and CBZ monotherapy demonstrated similar efficacy for treatment of partial epilepsy and were found to be well tolerated. PMID:26798511

  2. Extracorporeal Shockwave Lithotripsy Monotherapy is not Adequate for Management of Staghorn Renal Calculi.

    PubMed

    Koko, Abdelmoniem K; Onuora, Vincent C; Al Turki, Mohammed A; Mesbed, Ahmed H; Al Jawini, Nasser A

    2003-01-01

    Between 1990 and 1999 a total of 186 patients with staghorn renal stones were treated in our unit. Of them, 76 patients were managed by extra-corporeal shockwave lithotripsy (ESWL) alone using a third generation Siemen's Lithostar Plus lithotriptor. Sixty-one of these patients who completed a follow-up of 41 months formed the subjects of this study. ESWL was done after routine stenting of the affected side in all cases except one. The mean number of ESWL sessions was 5.2, delivering an average 15,940 shocks per patient. The average hospital stay was 21.68 days and the duration of the treatment was 1-41 months (mean 6.75 months). Significant complications occurred in 35 patients (57.4%) eight of whom sustained multiple significant complications. A total of 162 auxiliary procedures were used in conjunction with ESWL and in the management of complications. The stone free rate at three months was 18%, but rose by the end of the treatment period (41 months) to 63.9%. Our study indicates that ESWL monotherapy is associated with high morbidity rates, high rates of unplanned invasive procedures as well as prolonged treatment periods and hospitalization. Thus, ESWL monotherapy is not adequate for the management of staghorn calculi.

  3. Salmonella Bacterial Monotherapy Reduces Autochthonous Prostate Tumor Burden in the TRAMP Mouse Model.

    PubMed

    Kazmierczak, Robert A; Gentry, Bettina; Mumm, Tyler; Schatten, Heide; Eisenstark, Abraham

    2016-01-01

    Attenuated Salmonella typhimurium injected in the circulatory system of mammals selectively targets tumors. Using weekly intraperitoneal injections of attenuated Salmonella strain CRC2631, we tested for regression and/or inhibition of tumor development in the TRAMP prostate tumor mouse model, which utilizes SV40 early region expression for autochthonous formation of prostate tumors that progress into metastatic, poorly differentiated prostatic carcinomas in an immunocompetent murine model. Thirteen weekly intraperitoneal administrations of 105-107 CFU CRC2631 into 10 week old mice were well tolerated by the TRAMP model. Sacrifice and histological analysis of TRAMP prostates at 22 weeks indicated that Salmonella monotherapy at administrated levels decrease visible tumor size (>29%) but did not significantly inhibit previously described SV40 expression-driven TRAMP tumor progression to undifferentiated carcinomas when histologically examined. In conclusion, this work demonstrates baseline results for CRC2631 Salmonella monotherapy using the immunocompetent TRAMP prostate tumor model in preparation for study of combination therapies that resolve autochthonously generated TRAMP prostate tumors, further reduce tumor size, or inhibit prostate tumor progression. PMID:27504973

  4. Efficacy and Safety of Levetiracetam and Carbamazepine as Monotherapy in Partial Seizures.

    PubMed

    Suresh, Swaroop Hassan; Chakraborty, Ananya; Virupakshaiah, Akash; Kumar, Nithin

    2015-01-01

    Introduction. Levetiracetam (LEV) is a newer antiepileptic drug with better pharmacokinetic profile. Currently, it is frequently used for the treatment of partial seizures. The present study was undertaken to compare the efficacy and safety of LEV and Carbamazepine (CBZ) in partial epilepsy. Methods. This was a prospective, open labeled, randomized study. It was conducted in participants suffering from partial seizures after the approval of ethics committee and written informed consent. The first group received Tab LEV (500 to 3000 mg/day) and the second group received Tab CBZ (300 to 600 mg/day). The primary outcomes were efficacy and safety. The secondary outcome was the Quality of Life (QOL). Efficacy was assessed by comparing the seizure freedom rates at the end of 6 months. Safety profile was evaluated by comparing the adverse effects. QOL was assessed by QOLIE-10 scale. Results. The overall seizure freedom rate at the end of 6 months was 71.42% in CBZ group compared to 78.57% in LEV group (p = 0.2529). Both LEV and CBZ reported a similar incidence of adverse reactions. LEV group reported more behavioral changes like increased aggression and anxiety. Also, it showed better QOL compared to the CBZ group. Conclusion. LEV monotherapy and CBZ monotherapy demonstrated similar efficacy for treatment of partial epilepsy and were found to be well tolerated. PMID:26798511

  5. Presumed Allergic Proctocolitis Resolves with Probiotic Monotherapy: A Report of 4 Cases.

    PubMed

    Martin, Victoria J; Shreffler, Wayne G; Yuan, Qian

    2016-01-01

    BACKGROUND The prevalence of allergic diseases has been dramatically rising in the United States and other developed nations over recent decades. Growing evidence suggests a partial role for the microbiome in the development of these allergic diseases. Food protein-induced allergic proctocolitis (AP) (also referred to as cow's milk protein intolerance or allergy) is among the earliest and most common food allergic diseases of infancy, yet its pathophysiology is not well understood. The currently accepted clinical practice is to restrict the diet until 12 months of age. CASE REPORT We present 4 cases of clinically diagnosed AP whose symptoms quickly and completely resolved with probiotic Lactobacillus rhamnosus GG (LGG) monotherapy. All 4 infants avoided any dietary restrictions. The range of time from probiotic initiation to symptom resolution was 7-28 days. CONCLUSIONS These cases suggest an important role for the infant intestinal microbiome in the development of gastrointestinal mucosal food allergies such as AP. Prospective investigation of the intestinal microbiome in infants with AP may further our understanding of this disease's pathogenesis. The potential use of probiotic monotherapy in the treatment of AP also warrants further investigation. PMID:27568925

  6. Hypertonic saline monotherapy in children with perennial allergic rhinitis: a pilot study.

    PubMed

    Barberi, S; D'Auria, E; Bernardo, L; Ferrara, F; Pietra, B; Pinto, F; Ferrero, F; Ciprandi, G

    2016-01-01

    Perennial allergic rhinitis (PAR) is very common in children and has a relevant impact on their families. House dust mites (HDM) are the most relevant cause of PAR. The present pilot study aimed to evaluate whether hypertonic saline (3%) nasal spray as monotherapy is able to improve: nasal symptom severity and parental perception of rhinitis control, sleep, and school performance in HDM-mono-sensitized children with PAR. Globally, 25 children (13 males and 12 females; mean age 9.5±3.1 years) were treated for 3 weeks. They were visited at baseline, at the end of treatment, and after a 2-week follow-up. Hypertonic saline significantly reduced total symptom score, and improved the perception, according to their parents, of rhinitis control, sleep, and school performance. In conclusion, the present pilot study provided the first evidence that 3% hypertonic saline monotherapy was able to relieve nasal symptoms and parental perception of PAR impact as well as being safe and well tolerated.

  7. Effectiveness and safety of topical tacrolimus monotherapy for repigmentation in vitiligo: a comprehensive literature review*

    PubMed Central

    Sisti, Andrea; Sisti, Giovanni; Oranges, Carlo Maria

    2016-01-01

    Thus far, several small studies and case reports on the use of topical immunomodulators in vitiligo have been published. We undertook a comprehensive literature review, searching for studies evaluating clinical response to tacrolimus topical therapy for vitiligo. A search was performed on PubMed/Medline using the term “vitiligo”, combined with “topical” and “ointment”. Our inclusion criteria were: use of tacrolimus ointment as monotherapy to treat vitiligo. We found 29 studies from 2002 to 2014. Overall, 709 patients were treated in 29 studies. Pooling the lesions, 50% repigmentation of vitiligo patches was never achieved before 2 months of treatment, with a peak after 6 months of therapy. The best results were obtained on lesions of the cephalic region, especially the face, with tacrolimus 0.1% ointment two times daily. The percentage of non-responsive patients ranged from 0% to 14%. Treatment was generally well-tolerated; only localized adverse effects were reported. Our objective was to verify the effectiveness and safety of tacrolimus ointment monotherapy. It has good efficacy and tolerability. At present, only small trials and case series are available in the literature. Further, standardized investigations on a larger number of patients are needed. PMID:27192518

  8. Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy

    PubMed Central

    Ghorayeb, Nada El; Rondeau, Geneviève; Latour, Mathieu; Cohade, Christian; Olney, Harold; Lacroix, André; Perrotte, Paul; Sabourin, Alexis; Mazzuco, Tania L; Bourdeau, Isabelle

    2016-01-01

    Abstract Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic β-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients. PMID:27043680

  9. An observational study of first-line valproate monotherapy in focal epilepsy.

    PubMed

    Jedrzejczak, J; Kuncíková, M; Magureanu, S

    2008-01-01

    The objective of this multinational open-label, prospective study was to collect, under naturalistic conditions, data on the effectiveness and tolerability of first-line monotherapy with valproate in subjects newly or recently diagnosed with focal onset epilepsy. Patients were treated with sustained release sodium valproate. Seizure control and occurrence of adverse events were assessed after 6 months. Around 1192 adults and 792 children were included. The mean daily valproate dose was 683 mg in children and 987 mg in adults. The retention rate at 6 months was 90.0%. At this time, 77% of subjects were seizure free (83.7% of children and 72.7% of adults). Adverse events possibly related to treatment were observed in 10.2% of subjects, leading to treatment modification for 1.7%. The most common adverse events were weight gain, gastro-intestinal, neurological and skin disorders. Sustained release sodium valproate is effective and shows acceptable tolerability as first-line monotherapy in focal onset epilepsy.

  10. Salmonella Bacterial Monotherapy Reduces Autochthonous Prostate Tumor Burden in the TRAMP Mouse Model

    PubMed Central

    Kazmierczak, Robert A.; Gentry, Bettina; Mumm, Tyler; Schatten, Heide; Eisenstark, Abraham

    2016-01-01

    Attenuated Salmonella typhimurium injected in the circulatory system of mammals selectively targets tumors. Using weekly intraperitoneal injections of attenuated Salmonella strain CRC2631, we tested for regression and/or inhibition of tumor development in the TRAMP prostate tumor mouse model, which utilizes SV40 early region expression for autochthonous formation of prostate tumors that progress into metastatic, poorly differentiated prostatic carcinomas in an immunocompetent murine model. Thirteen weekly intraperitoneal administrations of 105–107 CFU CRC2631 into 10 week old mice were well tolerated by the TRAMP model. Sacrifice and histological analysis of TRAMP prostates at 22 weeks indicated that Salmonella monotherapy at administrated levels decrease visible tumor size (>29%) but did not significantly inhibit previously described SV40 expression-driven TRAMP tumor progression to undifferentiated carcinomas when histologically examined. In conclusion, this work demonstrates baseline results for CRC2631 Salmonella monotherapy using the immunocompetent TRAMP prostate tumor model in preparation for study of combination therapies that resolve autochthonously generated TRAMP prostate tumors, further reduce tumor size, or inhibit prostate tumor progression. PMID:27504973

  11. Risk of mortality with concomitant use of tamoxifen and selective serotonin reuptake inhibitors: multi-database cohort study

    PubMed Central

    Donneyong, Macarius M; Bykov, Katsiaryna; Bosco-Levy, Pauline; Dong, Yaa-Hui; Levin, Raisa

    2016-01-01

    Objective To compare differences in mortality between women concomitantly treated with tamoxifen and selective serotonin reuptake inhibitors (SSRIs) that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) versus tamoxifen and other SSRIs. Design Population based cohort study. Setting Five US databases covering individuals enrolled in private and public health insurance programs from 1995 to 2013. Participants Two cohorts of women who started taking tamoxifen. In cohort 1, women started taking an SSRI during tamoxifen treatment. In cohort 2, women were already taking an SSRI when they started taking tamoxifen. Main outcome measures All cause mortality in each cohort in women taking SSRIs that are potent inhibitors of CYP2D6 (paroxetine, fluoxetine) versus other SSRIs. Propensity scores were used to match exposure groups in a variable ratio fashion. Results were measured separately for each cohort and combined hazard ratios calculated from Cox regression models across the two cohorts with random effects meta-analysis. Results There were 6067 and 8465 new users of tamoxifen in cohorts 1 and 2, respectively. Mean age was 55. A total of 991 and 1014 deaths occurred in cohorts 1 and 2 during a median follow-up of 2.2 (interquartile range 0.9-4.5) and 2.0 (0.8-3.9) years, respectively. The pooled hazard ratio for death for potent inhibitors (rate 58.6/1000 person years) compared with other SSRIs (rate 57.9/1000 person years) across cohorts 1 and 2 was 0.96 (95% confidence interval 0.88 to 1.06). Results were consistent across sensitivity analyses. Conclusion Concomitant use of tamoxifen and potent CYP2D6 inhibiting SSRIs versus other SSRIs was not associated with an increased risk of death. PMID:27694571

  12. Exosomal miR-221/222 enhances tamoxifen resistance in recipient ER-positive breast cancer cells.

    PubMed

    Wei, Yifang; Lai, Xiaofeng; Yu, Shentong; Chen, Suning; Ma, Yongzheng; Zhang, Yuan; Li, Huichen; Zhu, Xingmei; Yao, Libo; Zhang, Jian

    2014-09-01

    Recent studies have demonstrated that specific miRNAs, such as miR-221/222, may be responsible for tamoxifen resistance in breast cancer. Secreted miRNAs enclosed in exosomes can act as intercellular bio-messengers. Our objective is to investigate the role of secreted miR-221/222 in tamoxifen resistance of ER-positive breast cancer cells. Transmission electron microscopy analysis and nanoparticle tracking analysis were performed to determine the exosomes difference between MCF-7(TamR) (tamoxifen resistant) and MCF-7(wt) (tamoxifen sensitive) cells. PKH67 fluorescent labeling assay was used to detect exosomes derived from MCF-7(TamR) cells entering into MCF-7(wt) cells. The potential function of exosomes on tamoxifen resistance transmission was analyzed with cell viability, apoptosis ,and colony formation. MiRNA microarrays and qPCR were used to detect and compare the miRNAs expression levels in the two cells and exosomes. As the targets of miR-221/222, p27 and ERα were analyzed with western blot and qPCR. Compared with the MCF-7(wt) exosomes, there were significant differences in the concentration and size distribution of MCF-7(TamR) exosomes. MCF-7(wt) cells had an increased amount of exosomal RNA and proteins compared with MCF-7(TamR) cells. MCF-7(TamR) exosomes could enter into MCF-7(wt) cells, and then released miR-221/222. And the elevated miR-221/222 effectively reduced the target genes expression of P27 and ERα, which enhanced tamoxifen resistance in recipient cells. Our results are the first to show that secreted miR-221/222 serves as signaling molecules to mediate communication of tamoxifen resistance. PMID:25007959

  13. Mass spectrometric characterization of tamoxifene metabolites in human urine utilizing different scan parameters on liquid chromatography/tandem mass spectrometry.

    PubMed

    Mazzarino, Monica; de la Torre, Xavier; Di Santo, Roberto; Fiacco, Ilaria; Rosi, Federica; Botrè, Francesco

    2010-03-01

    Different liquid chromatographic/tandem mass spectrometric (LC/MS/MS) scanning techniques were considered for the characterization of tamoxifene metabolites in human urine for anti-doping purpose. Five different LC/MS/MS scanning methods based on precursor ion scan (precursor ion scan of m/z 166, 152 and 129) and neutral loss scan (neutral loss of 72 Da and 58 Da) in positive ion mode were assessed to recognize common ions or common losses of tamoxifene metabolites. The applicability of these methods was checked first by infusion and then by the injection of solution of a mixture of reference standards of four tamoxifene metabolites available in our laboratory. The data obtained by the analyses of the mixture of the reference standards showed that the five methods used exhibited satisfactory results for all tamoxifene metabolites considered at a concentration level of 100 ng/mL, whereas the analysis of blank urine samples spiked with the same tamoxifene metabolites at the same concentration showed that the neutral loss scan of 58 Da lacked sufficient specificity and sensitivity. The limit of detection in urine of the compounds studied was in the concentration range 10-100 ng/mL, depending on the compound structure and on the selected product ion. The suitability of these approaches was checked by the analysis of urine samples collected after the administration of a single dose of 20 mg of tamoxifene. Six metabolites were detected: 4-hydroxytamoxifene, 3,4-dihydroxytamoxifene, 3-hydroxy-4-methoxytamoxifene, N-demethyl-4-hydroxytamoxifene, tamoxifene-N-oxide and N-demethyl-3-hydroxy-4-methoxytamoxifene, which is in conformity to our previous work using a time-of-flight (TOF) mass spectrometer in full scan acquisition mode. PMID:20187079

  14. P-glycoprotein (ABCB1) transports the primary active tamoxifen metabolites endoxifen and 4-hydroxytamoxifen and restricts their brain penetration.

    PubMed

    Iusuf, Dilek; Teunissen, Sebastiaan F; Wagenaar, Els; Rosing, Hilde; Beijnen, Jos H; Schinkel, Alfred H

    2011-06-01

    P-glycoprotein (P-gp, ABCB1) is a highly efficient drug efflux pump expressed in brain, liver, and small intestine, but also in tumor cells, that affects pharmacokinetics and confers therapy resistance for many anticancer drugs. The aim of this study was to investigate the impact of P-gp on tamoxifen and its primary active metabolites, 4-hydroxytamoxifen, N-desmethyltamoxifen, and endoxifen. We used in vitro transport assays and Abcb1a/1b(-/-) mice to investigate the impact of P-gp on the oral availability and brain penetration of tamoxifen and its metabolites. Systemic exposure of tamoxifen and its metabolites after oral administration of tamoxifen (50 mg/kg) was not changed in the absence of P-gp. However, brain accumulation of tamoxifen, 4-hydroxytamoxifen, and N-desmethyltamoxifen were modestly, but significantly (1.5- to 2-fold), increased. Endoxifen, however, displayed a 9-fold higher brain penetration at 4 h after administration. Endoxifen was transported by P-gp in vitro. Upon direct oral administration of endoxifen (20 mg/kg), systemic exposure was slightly decreased in Abcb1a/1b(-/-) mice, but brain accumulation of endoxifen was dramatically increased (up to 23-fold at 4 h after administration). Shortly after high-dose intravenous administration (5 or 20 mg/kg), endoxifen brain accumulation was increased only 2-fold in Abcb1a/1b(-/-) mice compared with wild-type mice, suggesting a partial saturation of P-gp at the blood-brain barrier. Endoxifen, the clinically most relevant metabolite of tamoxifen, is a P-gp substrate in vitro and in vivo, where P-gp limits its brain penetration. P-gp might thus be relevant for tamoxifen/endoxifen resistance of P-gp-positive breast cancer and tumors positioned behind a functional blood-brain barrier. PMID:21378205

  15. Psychosocial and Physical Effects of Adjuvant Chemotherapy

    PubMed Central

    Hislop, Thomas Gregory; Elwood, J. Mark; Waxler-Morrison, Nancy; Ragaz, Joseph; Skippen, Diane Hazel; Turner, I.D.

    1991-01-01

    Breast cancer patients younger than 55 completed a questionnaire on psychosocial factors and physical side effects shortly after diagnosis and 9 to 15 months after diagnosis. Those who had used adjuvant chemotherapy were more likely than those who had not to report physical side effects; there was little difference in psychosocial factors. Recent users were more likely than ex-users to report physical side effects, difficulties with domestic chores, and improvement in psychosocial factors. PMID:21229020

  16. Inflammatory responses following intramuscular and subcutaneous immunization with aluminum-adjuvanted or non-adjuvanted vaccines.

    PubMed

    Kashiwagi, Yasuyo; Maeda, Mika; Kawashima, Hisashi; Nakayama, Tetsuo

    2014-06-01

    Aluminum-adjuvanted vaccines are administered through an intramuscular injection (IM) in the US and EU, however, a subcutaneous injection (SC) has been recommended in Japan because of serious muscle contracture previously reported following multiple IMs of antibiotics. Newly introduced adjuvanted vaccines, such as the human papillomavirus (HPV) vaccines, have been recommended through IM. In the present study, currently available vaccines were evaluated through IM in mice. Aluminum-adjuvanted vaccines induced inflammatory nodules at the injection site, which expanded into the intra-muscular space without any muscle degeneration or necrosis, whereas non-adjuvanted vaccines did not. These nodules consisted of polymorph nuclear neutrophils with some eosinophils within the initial 48h, then monocytes/macrophages 1 month later. Inflammatory nodules were observed 6 months after IM, had decreased in size, and were absorbed 12 months after IM, which was earlier than that after SC. Cytokine production was examined in the injected muscular tissues and AS04 adjuvanted HPV induced higher IL-1β, IL-6, KC, MIP-1, and G-CSF levels in muscle tissues than any other vaccine, but similar serum cytokine profiles were observed to those induced by the other vaccines. Currently available vaccines did not induce muscular degeneration or fibrotic scar as observed with muscle contracture caused by multiple IMs of antibiotics in the past.

  17. Cost-effectiveness of dipeptidyl peptidase-4 inhibitor monotherapy in elderly type 2 diabetes patients in Thailand

    PubMed Central

    Permsuwan, Unchalee; Dilokthornsakul, Piyameth; Saokaew, Surasak; Thavorn, Kednapa; Chaiyakunapruk, Nathorn

    2016-01-01

    Background The management of type 2 diabetes mellitus (T2DM) in elderly population poses many challenges. Dipeptidyl peptidase-4 (DPP-4) inhibitors show particular promise due to excellent tolerability profiles, low risk of hypoglycemia, and little effect on body weight. This study evaluated, from the health care system’s perspective, the long-term cost-effectiveness of DPP-4 inhibitor monotherapy vs metformin and sulfonylurea (SFU) monotherapy in Thai elderly T2DM patients. Methods The clinical efficacy was estimated from a systematic review and meta-analysis. Baseline cohort characteristics and cost parameters were obtained from published studies and hospital databases in Thailand. A validated IMS CORE Diabetes Model version 8.5 was used to project clinical and economic outcomes over a lifetime horizon using a 3% annual discount rate. Costs were expressed in 2014 Thai Baht (THB) (US dollar value). Incremental cost-effectiveness ratios were calculated. Base-case assumptions were assessed through several sensitivity analyses. Results For treating elderly T2DM patients, DPP-4 inhibitors were more expensive and less effective, ie, a dominated strategy, than the metformin monotherapy. Compared with SFU, treatment with DPP-4 inhibitors gained 0.031 more quality-adjusted life years (QALYs) at a total cost incurred over THB113,701 or US$3,449.67, resulting in an incremental cost-effectiveness ratio of THB3.63 million or US$110,133.50 per QALY. At the acceptable Thai ceiling threshold of THB160,000/QALY (US$4,854.37/QALY), DPP-4 inhibitors were not a cost-effective treatment. Conclusion DPP-4 inhibitor monotherapy is not a cost-effective treatment for elderly T2DM patients compared with metformin monotherapy and SFU monotherapy, given current resource constraints in Thailand. PMID:27703387

  18. Utility of adjuvant systemic therapy in melanoma

    PubMed Central

    Eggermont, A. M. M.; Testori, A.; Marsden, J.; Hersey, P.; Quirt, I.; Petrella, T.; Gogas, H.; MacKie, R. M.; Hauschild, A.

    2009-01-01

    The lack of effective drugs in stage IV melanoma has impacted the effectiveness of adjuvant therapies in stage II/III disease. To date, chemotherapy, immunostimulants and vaccines have been used with minimal success. Interferon (IFN) has shown an effect on relapse-free survival (RFS) in several clinical trials; however, without a clinically significant effect on overall survival (OS). A recently conducted meta-analysis demonstrated prolongation of disease-free survival (DFS) in 7% and OS benefit in 3% of IFN-treated patients when compared with observation-only patients. There were no clear differences for the dose and duration of treatment observed. Observation is still an appropriate control arm in adjuvant clinical trials. Regional differences exist in Europe in the adjuvant use of IFN. In Northwest Europe, IFN is infrequently prescribed. In Central and Mediterranean Europe, dermatologists commonly prescribe low-dose IFN therapy for AJCC stage II and III disease. High-dose IFN regimens are not commonly used. The population of patients that may benefit from IFN needs to be further characterised, potentially by finding biomarkers that can predict response. Such studies are ongoing. PMID:19617295

  19. Adjuvant and neoadjuvant treatment in pancreatic cancer

    PubMed Central

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

    2012-01-01

    Pancreatic adenocarcinoma is one of the most aggressive human malignancies, ranking 4th among causes for cancer-related death in the Western world including the United States. Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy. Currently there is no consensus around the world on what constitutes “standard” adjuvant therapy for pancreatic cancer. This controversy derives from several studies, each fraught with its own limitations. Standards of care also vary somewhat with regard to geography and economy, for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe. Regardless of the efforts in adjuvant and neoadjuvant improved therapy, the major goal to combat pancreatic cancer is to find diagnostic markers, identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients. In this review, authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients. PMID:22529684

  20. Recent Advances of Vaccine Adjuvants for Infectious Diseases

    PubMed Central

    Nguyen, Minh Trang

    2015-01-01

    Vaccines are the most effective and cost-efficient method for preventing diseases caused by infectious pathogens. Despite the great success of vaccines, development of safe and strong vaccines is still required for emerging new pathogens, re-emerging old pathogens, and in order to improve the inadequate protection conferred by existing vaccines. One of the most important strategies for the development of effective new vaccines is the selection and usage of a suitable adjuvant. Immunologic adjuvants are essential for enhancing vaccine potency by improvement of the humoral and/or cell-mediated immune response to vaccine antigens. Thus, formulation of vaccines with appropriate adjuvants is an attractive approach towards eliciting protective and long-lasting immunity in humans. However, only a limited number of adjuvants is licensed for human vaccines due to concerns about safety and toxicity. We summarize current knowledge about the potential benefits of adjuvants, the characteristics of adjuvants and the mechanisms of adjuvants in human vaccines. Adjuvants have diverse modes of action and should be selected for use on the basis of the type of immune response that is desired for a particular vaccine. Better understanding of current adjuvants will help exploring new adjuvant formulations and facilitate rational design of vaccines against infectious diseases. PMID:25922593

  1. Transporting antitumor drug tamoxifen and its metabolites, 4-hydroxytamoxifen and endoxifen by chitosan nanoparticles.

    PubMed

    Agudelo, Daniel; Sanyakamdhorn, Sriwanna; Nafisi, Shoherh; Tajmir-Riahi, Heidar-Ali

    2013-01-01

    Synthetic and natural polymers are often used as drug delivery systems in vitro and in vivo. Biodegradable chitosan of different sizes were used to encapsulate antitumor drug tamoxifen (Tam) and its metabolites 4-hydroxytamoxifen (4-Hydroxytam) and endoxifen (Endox). The interactions of tamoxifen and its metabolites with chitosan 15, 100 and 200 KD were investigated in aqueous solution, using FTIR, fluorescence spectroscopic methods and molecular modeling. The structural analysis showed that tamoxifen and its metabolites bind chitosan via both hydrophilic and hydrophobic contacts with overall binding constants of K(tam-ch-15) = 8.7 ( ± 0.5) × 10(3) M(-1), K(tam-ch-100) = 5.9 (± 0.4) × 10(5) M(-1), K(tam-ch-200) = 2.4 (± 0.4) × 10(5) M(-1) and K(hydroxytam-ch-15) = 2.6(± 0.3) × 10(4) M(-1), K(hydroxytam - ch-100) = 5.2 ( ± 0.7) × 10(6) M(-1) and K(hydroxytam-ch-200) = 5.1 (± 0.5) × 10(5) M(-1), K(endox-ch-15) = 4.1 (± 0.4) × 10(3) M(-1), K(endox-ch-100) = 1.2 (± 0.3) × 10(6) M(-1) and K(endox-ch-200) = 4.7 (± 0.5) × 10(5) M(-1) with the number of drug molecules bound per chitosan (n) 2.8 to 0.5. The order of binding is ch-100>200>15 KD with stronger complexes formed with 4-hydroxytamoxifen than tamoxifen and endoxifen. The molecular modeling showed the participation of polymer charged NH2 residues with drug OH and NH2 groups in the drug-polymer adducts. The free binding energies of -3.46 kcal/mol for tamoxifen, -3.54 kcal/mol for 4-hydroxytamoxifen and -3.47 kcal/mol for endoxifen were estimated for these drug-polymer complexes. The results show chitosan 100 KD is stronger carrier for drug delivery than chitosan-15 and chitosan-200 KD. PMID:23527310

  2. The role of captopril and losartan in prevention and regression of tamoxifen-induced resistance of breast cancer cell line MCF-7: an in vitro study.

    PubMed

    Namazi, Soha; Rostami-Yalmeh, Javad; Sahebi, Ebrahim; Jaberipour, Mansooreh; Razmkhah, Mahboobeh; Hosseini, Ahmad

    2014-06-01

    Innate and acquired tamoxifen (TAM) resistance in estrogen receptor positive (ER+) breast cancer is an important problem in adjuvant endocrine therapy. The underlying mechanisms of TAM resistance is yet unknown. In the present study, we evaluated the role of renin-angiotensin system (RAS) in the acquisition of TAM resistance in human breast cancer cell line MCF-7, and the potential role of captopril and captopril+losartan combination in the prevention and reversion of the TAM resistant phenotype. MCF-7 cells were continuously exposed to 1 μmol/L TAM to develop TAM resistant cells (TAM-R). MTT cell viability assay was used to determine the growth response of MCF-7 and TAM-R cells, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess angiotensin I converting enzyme (ACE), angiotensin II receptor type-1 and type-2 (AGTR1 and AGTR2) mRNA expressions. Preventive and therapeutic effects of RAS blockers - captopril and losartan - were examined on MCF-7 and TAM-R cells. Based on qRT-PCR, TAM-R cells compared to MCF-7 cells, had a mean ± SD fold increase of 319.1 ± 204.1 (P = 0.002) in production of ACE mRNA level, 2211.8 ± 777.9 (P = 0.002) in AGTR1 mRNA level, and 265.9 ± 143.9 (P = 0.037) in production of AGTR2 mRNA level. The combination of either captopril or captopril+losartan with TAM led to the prevention and even reversion of TAM resistant phenotype.

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

    PubMed Central

    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

    Objectives This study examined the relationship between positive and negative affect, depressive symptoms, and cognitive performance. Methods The sample consisted of 1,479 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 (STAR). At each annual visit, women completed a standardized neuropsychological battery and self-report measures of affect and depression. Data from 3 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. Results Higher positive affect was associated with better letter fluency (p=0.006) and category fluency (p<0.0001). Higher negative affect was associated with worse global cognitive function (p<0.0001), verbal memory (CVLT List B; p=0.002), and spatial ability (p<0.0001). Depressive symptoms were negatively associated with verbal knowledge (p=0.004), figural memory (p<0.0001), and verbal memory (p’s≤0.0001). Discussion Findings are consistent with some prior research demonstrating a link between 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. PMID:23237718

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

    PubMed Central

    2012-01-01

    Background Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Methods Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Results Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0

  5. ERα-XPO1 Cross Talk Controls Tamoxifen Sensitivity in Tumors by Altering ERK5 Cellular Localization

    PubMed Central

    Wrobel, Kinga; Zhao, Yiru Chen; Kulkoyluoglu, Eylem; Chen, Karen Lee Ann; Hieronymi, Kadriye; Holloway, Jamie; Li, Sarah; Ray, Tania; Ray, Partha Sarathi; Landesman, Yosef; Lipka, Alexander Edward; Smith, Rebecca Lee

    2016-01-01

    Most breast cancer deaths occur in women with recurrent, estrogen receptor (ER)-α(+), metastatic tumors. There is a critical need for therapeutic approaches that include novel, targetable mechanism-based strategies by which ERα (+) tumors can be resensitized to endocrine therapies. The objective of this study was to validate a group of nuclear transport genes as potential biomarkers to predict the risk of endocrine therapy failure and to evaluate the inhibition of XPO1, one of these genes as a novel means to enhance the effectiveness of endocrine therapies. Using advanced statistical methods, we found that expression levels of several of nuclear transport genes including XPO1 were associated with poor survival and predicted recurrence of tamoxifen-treated breast tumors in human breast cancer gene expression data sets. In mechanistic studies we showed that the expression of XPO1 determined the cellular localization of the key signaling proteins and the response to tamoxifen. We demonstrated that combined targeting of XPO1 and ERα in several tamoxifen-resistant cell lines and tumor xenografts with the XPO1 inhibitor, Selinexor, and tamoxifen restored tamoxifen sensitivity and prevented recurrence in vivo. The nuclear transport pathways have not previously been implicated in the development of endocrine resistance, and given the need for better strategies for selecting patients to receive endocrine modulatory reagents and improving therapy response of relapsed ERα(+) tumors, our findings show great promise for uncovering the role these pathways play in reducing cancer recurrences. PMID:27533791

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

    PubMed

    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.

  7. Induction of transforming growth factor beta by the antiestrogens droloxifene, tamoxifen, and toremifene in MCF-7 cells.

    PubMed

    Knabbe, C; Zugmaier, G; Schmahl, M; Dietel, M; Lippman, M E; Dickson, R B

    1991-01-01

    We have previously shown that transforming growth factor beta (TGF beta) is a hormonally regulated negative growth factor in estrogen responsive MCF-7 human breast cancer cells. We have now compared the antiestrogens tamoxifen, droloxifene (3-hydroxytamoxifen), and toremifene in their ability to induce the secretion of autoinhibitory TGF beta by MCF-7 cells. The main results are as follows: induction of TGF beta secretion by droloxifene is about two to three times higher than by identical concentrations of tamoxifen or toremifene. A 5-10 times higher concentration of tamoxifen or toremifene than droloxifene is necessary to reach a similar induction of TGF beta secretion. In contrast to tamoxifen, intermittent application of droloxifene is as effective as continuous treatment in inducing TGF beta secretion. We conclude from these data that TGF beta proteins represent markers of antiestrogen action and might also play a pivotal role in their mechanism of action. Droloxifene is a more effective inducer of TGF beta and a more potent growth inhibitor for estrogen responsive human breast cancer cells than tamoxifen and toremifene in vitro. Therefore, droloxifene might also possess a higher antiestrogenic potential in treatment of human breast cancer.

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

    PubMed Central

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

    2016-01-01

    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. PMID:26923756

  9. Improved persistence and adherence to diuretic fixed-dose combination therapy compared to diuretic monotherapy

    PubMed Central

    Patel, Bimal V; Remigio-Baker, Rosemay A; Thiebaud, Patrick; Preblick, Ronald; Plauschinat, Craig

    2008-01-01

    Background Diuretics are recommended as initial treatment for hypertension. Several studies have suggested suboptimal persistence and adherence to thiazide diuretic monotherapy; this study compared patient persistence and adherence with hydrochlorothiazide (HCTZ) monotherapy to fixed-dose combinations containing HCTZ. Methods Patients with at least one prescription claim during 2001 to 2003 for either HCTZ or one of the following fixed-dose combinations: angiotensin-receptor blockers/HCTZ (ARB/HCTZ), angiotensin-converting enzyme inhibitor/HCTZ (ACEI/HCTZ), or beta blockers/HCTZ (BB/HCTZ) were identified. Patients were required to be continuously benefit-eligible six months pre- and one year post-index date, and to have no prescription claims for any antihypertensive therapy six months prior to the index date. Patients were followed for one year to assess persistence, medication possession ratio (MPR), adherence (MPR >80%), and proportion of days covered (PDC) with initial antihypertensive therapy. Logistic regression was used to calculate adjusted odds ratios for persistence, adherence and PDC, adjusted for age, gender, business segment, RxRisk disease categories, average co-pay and concurrent cardiovascular-related medication utilization. Results The study cohort consisted of 48,212 patients; 72.5% used HCTZ, 13.2% ACEI/HCTZ, 9.3% ARB/HCTZ, and 5.0% BB/HCTZ. Mean age was 53.7 years and 66.5% were female. A significantly lower proportion of patients using HCTZ (29.9%) remained persistent with therapy at 12 months compared with ARB/HCTZ (52.6%; OR = 0.37, CI = 0.36, 0.38), ACEI/HCTZ (51.4%; OR = 0.38, CI = 0.37, 0.39), and BB/HCTZ (51.9%; OR = 0.38, 0.37, 0.40). Similarly, PDC was lower for HCTZ patients (32.5%) as compared to ARB/HCTZ (53.7%; OR = 0.39, CI = 0.37, 0.40), ACEI/HCTZ (50.9%; OR = 0.42, CI = 0.40, 0.43), and BB/HCTZ (51.3%; OR = 0.44, CI 0.42, 0.45). MPR was also significantly lower for HCTZ patients as compared to those using fixed-dose combination

  10. Adjuvant chemotherapy for rectal cancer: Is it needed?

    PubMed Central

    Milinis, Kristijonas; Thornton, Michael; Montazeri, Amir; Rooney, Paul S

    2015-01-01

    Adjuvant chemotherapy has become a standard treatment of advanced rectal cancer in the West. The benefits of adjuvant chemotherapy after surgery alone have been well established. However, controversy surrounds the use adjuvant chemotherapy in patients who received preoperative chemoradiotherapy, despite it being recommended by a number of international guidelines. Results of recent multicentre randomised control trials showed no benefit of adjuvant chemotherapy in terms of survival and rates of distant metastases. However, concerns exist regarding the quality of the studies including inadequate staging modalities, out-dated chemotherapeutic regimens and surgical approaches and small sample sizes. It has become evident that not all the patients respond to adjuvant chemotherapy and more personalised approach should be employed when considering the benefits of adjuvant chemotherapy. The present review discusses the strengths and weaknesses of the current evidence-base and suggests improvements for future studies. PMID:26677436

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

    PubMed Central

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

    2007-01-01

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

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

    PubMed

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

    2013-11-01

    Tamoxifen (Tam) has a broad spectrum of anticancer activity, but is limited in clinical application. The aim of this study was to explore the smart pH-responsive drug delivery system (DDS) based on chitosan (CH) nanoparticles (NPs) for its potential in enabling more intelligent controlled release and enhancing chemotherapeutic efficiency of Tamoxifen. Tamoxifen was loaded onto CH-nanoparticles by forming complexes and Tamoxifen was released from the DDS much more rapidly at pH 4.0 and 6.0 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. Tamoxifen-loaded CH nanoparticles induced remarkable improvement in anticancer activity, as demonstrated by MTT-assay, AO/EtBr and Hoechst nuclear staining. Furthermore, the possible signaling pathway was explored by RT-PCR. For instance, in human breast cancer MCF-7 cells, it was demonstrated that Tamoxifen-loaded CH nanoparticles increase intracellular concentration of Tamoxifen and enhance its anticancer efficiency by inducing apoptosis in a caspase-dependent manner, indicating that drug loaded nanoparticles could act as an efficient DDS importing Tamoxifen into target cancer cells. PMID:23787278

  13. Tamoxifen inhibits tumor cell invasion and metastasis in mouse melanoma through suppression of PKC/MEK/ERK and PKC/PI3K/Akt pathways

    SciTech Connect

    Matsuoka, Hiroshi; Tsubaki, Masanobu; Yamazoe, Yuzuru; Ogaki, Mitsuhiko; Satou, Takao; Itoh, Tatsuki; Kusunoki, Takashi; Nishida, Shozo

    2009-07-15

    In melanoma, several signaling pathways are constitutively activated. Among these, the protein kinase C (PKC) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Recently, it has been reported that tamoxifen, an anti-estrogen reagent, inhibits PKC signaling in estrogen-negative and estrogen-independent cancer cell lines. Thus, we investigated whether tamoxifen inhibited tumor cell invasion and metastasis in mouse melanoma cell line B16BL6. Tamoxifen significantly inhibited lung metastasis, cell migration, and invasion at concentrations that did not show anti-proliferative effects on B16BL6 cells. Tamoxifen also inhibited the mRNA expressions and protein activities of matrix metalloproteinases (MMPs). Furthermore, tamoxifen suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt through the inhibition of PKC{alpha} and PKC{delta} phosphorylation. However, other signal transduction factor, such as p38 mitogen-activated protein kinase (p38MAPK) was unaffected. The results indicate that tamoxifen suppresses the PKC/mitogen-activated protein kinase kinase (MEK)/ERK and PKC/phosphatidylinositol-3 kinase (PI3K)/Akt pathways, thereby inhibiting B16BL6 cell migration, invasion, and metastasis. Moreover, tamoxifen markedly inhibited not only developing but also clinically evident metastasis. These findings suggest that tamoxifen has potential clinical applications for the treatment of tumor cell metastasis.

  14. On vaccine's adjuvants and autoimmunity: Current evidence and future perspectives.

    PubMed

    Pellegrino, Paolo; Clementi, Emilio; Radice, Sonia

    2015-10-01

    Adjuvants are compounds incorporated into vaccines to enhance immunogenicity and the development of these molecules has become an expanding field of research in the last decades. Adding an adjuvant to a vaccine antigen leads to several advantages, including dose sparing and the induction of a more rapid, broader and strong immune response. Several of these molecules have been approved, including aluminium salts, oil-in-water emulsions (MF59, AS03 and AF03), virosomes and AS04. Adjuvants have recently been implicated in the new syndrome named "ASIA-Autoimmune/inflammatory Syndrome Induced by Adjuvants", which describes an umbrella of clinical conditions including post-vaccination adverse reactions. Recent studies implicate a web of mechanisms in the development of vaccine adjuvant-induced autoimmune diseases, in particular, in those associated with aluminium-based compounds. Fewer and unsystematised data are instead available about other adjuvants, despite recent evidence indicating that vaccines with different adjuvants may also cause specific autoimmune adverse reactions possible towards different pathogenic mechanisms. This topic is of importance as the specific mechanism of action of each single adjuvant may have different effects on the course of different diseases. Herein, we review the current evidence about the mechanism of action of currently employed adjuvants and discuss the mechanisms by which such components may trigger autoimmunity. PMID:26031899

  15. Rational design of small molecules as vaccine adjuvants.

    PubMed

    Wu, Tom Y-H; Singh, Manmohan; Miller, Andrew T; De Gregorio, Ennio; Doro, Francesco; D'Oro, Ugo; Skibinski, David A G; Mbow, M Lamine; Bufali, Simone; Herman, Ann E; Cortez, Alex; Li, Yongkai; Nayak, Bishnu P; Tritto, Elaine; Filippi, Christophe M; Otten, Gillis R; Brito, Luis A; Monaci, Elisabetta; Li, Chun; Aprea, Susanna; Valentini, Sara; Calabrό, Samuele; Laera, Donatello; Brunelli, Brunella; Caproni, Elena; Malyala, Padma; Panchal, Rekha G; Warren, Travis K; Bavari, Sina; O'Hagan, Derek T; Cooke, Michael P; Valiante, Nicholas M

    2014-11-19

    Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants.

  16. A study of the molecular conformations and the vibrational, 1H and 13C NMR spectra of the anticancer drug tamoxifen and triphenylethylene

    NASA Astrophysics Data System (ADS)

    Badawi, Hassan M.; Khan, Ibrahim

    2016-08-01

    The structural stability and the vibrational spectra of the anticancer drug tamoxifen and triphenylethylene were investigated by the DFT B3LYP/6-311G (d,p) calculations. Tamoxifen and triphenylethylene were predicted to exist predominantly as non-planar structures. The vibrational frequencies and the 1H and 13C NMR chemical shifts of the low energy structures of tamoxifen and triphenylethylene were computed at the DFT B3LYP level of theory. Complete vibrational assignments were provided by combined theoretical and experimental data of tamoxifen and triphenylethylene. The 1H and 13C NMR spectra of both molecules were interpreted by experimental and DFT calculated chemical shifts of the two molecules. The RMSD between experimental and theoretical 1H and 13C chemical shifts for tamoxifen is 0.29 and 4.72 ppm, whereas for triphenylethylene, it is 0.16 and 2.70 ppm, respectively.

  17. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody.

    PubMed

    Corti, Davide; Misasi, John; Mulangu, Sabue; Stanley, Daphne A; Kanekiyo, Masaru; Wollen, Suzanne; Ploquin, Aurélie; Doria-Rose, Nicole A; Staupe, Ryan P; Bailey, Michael; Shi, Wei; Choe, Misook; Marcus, Hadar; Thompson, Emily A; Cagigi, Alberto; Silacci, Chiara; Fernandez-Rodriguez, Blanca; Perez, Laurent; Sallusto, Federica; Vanzetta, Fabrizia; Agatic, Gloria; Cameroni, Elisabetta; Kisalu, Neville; Gordon, Ingelise; Ledgerwood, Julie E; Mascola, John R; Graham, Barney S; Muyembe-Tamfun, Jean-Jacques; Trefry, John C; Lanzavecchia, Antonio; Sullivan, Nancy J

    2016-03-18

    Ebola virus disease in humans is highly lethal, with case fatality rates ranging from 25 to 90%. There is no licensed treatment or vaccine against the virus, underscoring the need for efficacious countermeasures. We ascertained that a human survivor of the 1995 Kikwit Ebola virus disease outbreak maintained circulating antibodies against the Ebola virus surface glycoprotein for more than a decade after infection. From this survivor we isolated monoclonal antibodies (mAbs) that neutralize recent and previous outbreak variants of Ebola virus and mediate antibody-dependent cell-mediated cytotoxicity in vitro. Strikingly, monotherapy with mAb114 protected macaques when given as late as 5 days after challenge. Treatment with a single human mAb suggests that a simplified therapeutic strategy for human Ebola infection may be possible.

  18. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody.

    PubMed

    Corti, Davide; Misasi, John; Mulangu, Sabue; Stanley, Daphne A; Kanekiyo, Masaru; Wollen, Suzanne; Ploquin, Aurélie; Doria-Rose, Nicole A; Staupe, Ryan P; Bailey, Michael; Shi, Wei; Choe, Misook; Marcus, Hadar; Thompson, Emily A; Cagigi, Alberto; Silacci, Chiara; Fernandez-Rodriguez, Blanca; Perez, Laurent; Sallusto, Federica; Vanzetta, Fabrizia; Agatic, Gloria; Cameroni, Elisabetta; Kisalu, Neville; Gordon, Ingelise; Ledgerwood, Julie E; Mascola, John R; Graham, Barney S; Muyembe-Tamfun, Jean-Jacques; Trefry, John C; Lanzavecchia, Antonio; Sullivan, Nancy J

    2016-03-18

    Ebola virus disease in humans is highly lethal, with case fatality rates ranging from 25 to 90%. There is no licensed treatment or vaccine against the virus, underscoring the need for efficacious countermeasures. We ascertained that a human survivor of the 1995 Kikwit Ebola virus disease outbreak maintained circulating antibodies against the Ebola virus surface glycoprotein for more than a decade after infection. From this survivor we isolated monoclonal antibodies (mAbs) that neutralize recent and previous outbreak variants of Ebola virus and mediate antibody-dependent cell-mediated cytotoxicity in vitro. Strikingly, monotherapy with mAb114 protected macaques when given as late as 5 days after challenge. Treatment with a single human mAb suggests that a simplified therapeutic strategy for human Ebola infection may be possible. PMID:26917593

  19. Combination With Low-dose Dextromethorphan Improves the Effect of Amlodipine Monotherapy in Clinical Hypertension

    PubMed Central

    Yin, Wei-Hsian; Chen, Pei; Yeh, Hung-I; Wang, Kuo-Yang; Hung, Yi-Jen; Tseng, Wei-Kung; Wen, Ming-Shien; Wu, Tao-Cheng; Wu, Chau-Chung; Cheng, Shu-Meng; Chen, Jaw-Wen

    2016-01-01

    Abstract The combination of low rather than high dose of dextromethorphan (DXM) with amlodipine (AM) could improve blood pressure (BP) reduction in hypertensive animals. The study aimed to evaluate the feasibility of different doses of DXM combined with standard AM treatment in clinical hypertension. This was a prospective, 14-week, dose-escalation, multicenter study. After 2-week run-in period with AM 5 mg/day, hypertensive patients who got the BP goal of 140/90 mmHg kept receiving AM monotherapy for another 12 weeks. The nonresponders, while kept on AM 5 mg/day, received additional DXM treatment for 3 sequential dose-titrated periods with initially 2.5 mg/day, followed by 7.5 mg/day, and finally 30 mg/day. Each period was for 4 weeks. The patients at BP goal after each treatment period were defined as the responders and kept on the same combination till the end of the study. The responder rate of each treatment period was recorded. The changes of BP and serum antioxidant/endothelial markers between week 14 and week 2 were evaluated. Of the 103 patients initially enrolled, 89 entered the treatment period. In the 78 patients completing the study, 31 (40%) at BP goal after 2-week AM run-in kept on AM monotherapy (DXM0). The addition of 2.5 (DXM2.5) and 7.5 mg/day (DXM7.5) of DXM enabled BP goal achievement in 22 (47%) nonresponders to AM monotherapy including 16 (29%) with DXM2.5 and 6 (18%) with DXM7.5. Only 4 patients (16%) reached BP goal with the combination of DXM 30 mg/day (DXM30). Overall, 73% of the 78 patients reached BP goal at the end of the 14-week study. Mean systolic BP was reduced by 7.9% ± 7.0% with DXM2.5 (P < 0.001) and by 5.4% ± 2.4% with DXM7.5 (P = 0.003) respectively at week 14 from that at week 2, which was unchanged in either DXM0 or DXM30 group. Besides, the effects of combination treatment were particularly significant in the patients with impaired endothelial function suggested by reduced serum NOx level

  20. Ranibizumab in monotherapy and combined with photodynamic therapy for retinal angiomatous proliferation

    PubMed Central

    Arias, Luis; Gómez-Ulla, Francisco; Ruiz-Moreno, José M

    2016-01-01

    Purpose To compare the effects of intravitreal ranibizumab in monotherapy (group A) and combined with photodynamic therapy (PDT) with verteporfin (group B) in retinal angiomatous proliferation (RAP) treatment. Methods This was a multicentric, prospective, randomized clinical study conducted with parallel groups. The study eye in both groups received ranibizumab on days 1, 30, and 60 (loading dose); group B received PDT additionally on day 1. Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) testing and optical coherence tomography were performed monthly, and fluorescein angiography and indocyanine green angiography were performed quarterly. Retreatment criteria were leakage in fluorescein angiography or indocyanine green angiography, mean foveal thickness increase ≥100 µm, or VA decrease ≥5 letters. Results Twenty patients were recruited (ten patients in each group). Six eyes had previous treatment (three eyes in group A and three eyes in group B), so only 14 eyes were naïve. At 12-month follow-up, mean VA improved +1.5 letters in group A and +5.6 letters in group B (analysis of variance test; P>0.05). Two patients (20%) in both groups gained ≥15 letters (chi-square test; P>0.05). Mean changes in greatest linear dimension and in foveal thickness were not statistically significant between groups of treatment (analysis of variance test; P>0.05). Mean retreatments per patient were 1.8 (group A) and 0.9 (group B) (Mann–Whitney U-test; P>0.05). One patient died due to underlying disease not related to study medication. Conclusion Intravitreal ranibizumab administered in monotherapy or combined with PDT was efficacious in terms of VA stabilization in patients with RAP. PMID:27274190

  1. LONG-TERM TREATMENT WITH PEGVISOMANT AS MONOTHERAPY IN PATIENTS WITH ACROMEGALY: EXPERIENCE FROM ACROSTUDY

    PubMed Central

    Freda, Pamela U.; Gordon, Murray B.; Kelepouris, Nicky; Jonsson, Peter; Koltowska-Haggstrom, Maria; van der Lely, A.J.

    2015-01-01

    Objective To evaluate use of pegvisomant, a GH receptor antagonist, as monotherapy in ACROSTUDY, a global safety surveillance study set in 14 countries (373 sites). Methods A descriptive analysis of safety, magnetic resonance imaging (MRI) reading and treatment outcomes in 710 subjects who received at least one pegvisomant dose as monotherapy during and up to 5 years follow-up in ACROSTUDY. Results Subjects received 5.4 yr. (mean) of pegvisomant and were followed in ACROSTUDY 3.8 yr. (mean). A total of 1255 adverse events were reported in 345 subjects (48.6%). Serious adverse events were reported in 133 (18.7%) subjects including 22 deaths, none of which were attributed to pegvisomant use. Of 670 (94%) subjects with at least one liver function test reported in ACROSTUDY, 8 (1.2%) had reported increases in transaminases > 3X ULN. No liver failure was reported. Based on central MRI reading, 12 of 542 subjects (2.2%) had a confirmed increase or increase/decrease in tumor size. Injection-site reactions were reported in 2.3%. At 5 years of therapy, IGF-1 level was reported normal in 67.5% (mean dose 17.2 mg/day) and elevated in 29.9% (mean dose 19.8 mg/day). Subjects on 20 mg per day or more rose from 36% at 3 years to 41% at 5 years of therapy. Conclusions ACROSTUDY data indicate that pegvisomant used as sole medical therapy is safe and effective medical treatment for acromegaly. The reported low incidence of pituitary tumor size increase and liver enzyme elevations are reassuring and support the positive benefit–risk of pegvisomant therapy. PMID:25370326

  2. Lopinavir Plasma Concentrations and Virological Outcome with Lopinavir-Ritonavir Monotherapy in HIV-1-Infected Patients

    PubMed Central

    Ruiz-Valderas, Rosa; Sánchez-Rivas, Elena; Lluch, Amparo; Gutierrez-Valencia, Alicia; Torres-Cornejo, Almudena; BenMarzouk-Hidalgo, Omar J.; Viciana, Pompeyo

    2013-01-01

    There is significant intra- and intersubject variability in lopinavir (LPV) plasma concentrations after standard dosing; thus, this prospective study was conducted to determine whether low plasma LPV concentrations could be associated with virological outcome throughout lopinavir-ritonavir maintenance monotherapy (mtLPVr) in the clinical practice setting. If this hypothesis would be confirmed, LPV drug monitoring could improve the efficacy of mtLPVr regimens. Patients with previous virological failure (VF) on protease inhibitor-based regimens were also included if the genotypic resistance tests showed no major resistance mutation associated with reduced susceptibility to lopinavir-ritonavir. VF was defined as 2 consecutive determinations of HIV RNA levels of >200 copies/ml. Efficacy was analyzed by per-protocol analysis. Plasma LPV trough concentrations were measured by high-performance liquid chromatography using a UV detector. A total of 127 patients were included (22% with previous failure on protease inhibitors). After 96 weeks, the efficacy rate was 82.3% (95% confidence interval [CI95], 75.3 to 89.3%). Virological efficacy was independent of LPV plasma concentrations even when LPVr was given once daily. An adherence of <90% (HR, 4.4 [CI95, 1.78 to 10.8; P = 0.001]) and the presence of blips in the preceding 12 months (HR, 3.06 [CI95, 1.17 to 8.01; P = 0.022]) were the only variables independently associated with time to VF. These findings suggest that the LPV concentrations achieved with the standard doses of LPVr are sufficient to maintain virological control during monotherapy and that measurement of LPV concentrations is not useful for predicting virological outcome. Tight control of viral replication in the previous months and strict adherence throughout the mtLPVr regimen could improve the virological efficacy of this maintenance regimen. PMID:23716055

  3. Systemic corticosteroid monotherapy for clinically diagnosed acute rhinosinusitis: a randomized controlled trial

    PubMed Central

    Venekamp, Roderick P.; Bonten, Marc J.M.; Rovers, Maroeska M.; Verheij, Theo J.M.; Sachs, Alfred P.E.

    2012-01-01

    Background: Patients with acute rhinosinusitis are frequently encountered in primary care. Although corticosteroids are being increasingly used for symptom control, evidence supporting their use is inconclusive. We conducted a randomized controlled trial to examine the effectiveness of systemic corticosteroid monotherapy for clinically diagnosed, uncomplicated acute rhinosinusitis. Methods: We conducted a block-randomized, double-blind, placebo-controlled clinical trial at 54 primary care practices (68 family physicians) in the Netherlands between Dec. 30, 2008, and Apr. 28, 2011. Adult patients with clinically diagnosed acute rhinosinusitis were randomly assigned to receive either prednisolone 30 mg/d or placebo for 7 days and asked to complete a symptom diary for 14 days. The primary outcome measure was the proportion of patients with resolution of facial pain or pressure on day 7. Results: Of the 185 patients included in the trial (93 in the treatment group, 92 in the placebo group), 2 withdrew from the study and 9 were excluded from the primary analysis because of incomplete symptom reporting. The remaining 174 patients (88 in the treatment group, 86 in the placebo group) were included in the intention-to-treat analysis. The proportions of patients with resolution of facial pain or pressure on day 7 were 62.5% (55/88) in the prednisolone group and 55.8% (48/86) in the placebo group (absolute risk difference 6.7%, 95% confidence interval −7.9% to 21.2%). The groups were similar with regard to the decrease over time in the proportion of patients with total symptoms (combined symptoms of runny nose, postnasal discharge, nasal congestion, cough and facial pain) and health-related quality of life. Adverse events were mild and did not differ significantly between the groups. Interpretation: Systemic corticosteroid monotherapy had no clinically relevant beneficial effects among patients with clinically diagnosed acute rhinosinusitis. Netherlands Trial Register

  4. Discontinuing antiepileptic drugs in patients who are seizure free on monotherapy

    PubMed Central

    Specchio, L; Tramacere, L; La Neve, A; Beghi, E

    2002-01-01

    Objectives: To assess the recurrence rate of epilepsy attributable to discontinuation of treatment in seizure free patients and to identify the risk factors for recurrence. Methods: 330 patients referred to an epilepsy centre who were seizure free for at least 2 years while on stable monotherapy were the study population. Discontinuation of antiepileptic drugs (AEDs) was proposed to all eligible patients or to their carers after discussion of the risks and benefits. Depending on whether they accepted or refused treatment withdrawal, the patients were stratified into two cohorts and followed up until seizure relapse or 31 March 1999, whichever came first. For each patient, records were taken of the main demographic and clinical variables. Results: The sample comprised 225 patients who entered the discontinuation programme and 105 who decided to continue treatment. Twenty nine patients (28%) continuing treatment had a relapse, compared with 113 (50%) of those entering the withdrawal programme. For patients continuing treatment, the probability of remission was 95% at 6 months, 91% at 12 months, 82% at 24 months, 80% at 36 months, and 68% at 60 months. The corresponding values for patients discontinuing treatment were 88%, 74%, 57%, 51%, and 48%. After adjusting for the principal prognostic factors, in patients discontinuing AEDs the risk of seizure relapse was 2.9 times that of patients continuing treatment. A relation was also found between relapse and duration of active disease, number of years of remission while on treatment, and abnormal psychiatric findings. Conclusions: Seizure free referral patients on stable monotherapy who elect to withdraw drug treatment are at higher risk of seizure relapse compared with patients continuing treatment. Severity of disease and seizure free period are significant prognostic factors. PMID:11784819

  5. Prevalence and Correlates of Cigarette Smoking among Chinese Schizophrenia Inpatients Receiving Antipsychotic Mono-Therapy

    PubMed Central

    Xu, Yan-Min; Chen, Hong-Hui; Li, Fu; Deng, Fang; Liu, Xiao-Bo; Yang, Hai-Chen; Qi, Li-Guo; Guo, Jin-Hong; Liu, Tie-Bang

    2014-01-01

    Objective To investigate the prevalence rate of cigarette smoking and its socio-demographic and clinical correlates in Chinese schizophrenia inpatients receiving antipsychotic mono-therapy. Methods This study was a cross-sectional, two-site, hospital-based survey. Four hundred and twenty-nine schizophrenia patients (male/female: 66.9% vs. 33.1%) were consecutively recruited from psychosis inpatient wards of two large specialty psychiatric hospitals in mainland China. Patients were assessed using a cigarette smoking questionnaire, the Positive and Negative Symptom Scale, the Simpson Angus Scale, the Barnes Akathisia Rating Scale, and the Abnormal Involuntary Movement Scale. Socio-demographic and other clinical data were also collected. We calculated the prevalence of current smoking in our sample as well as its indirectly standardized prevalence ratio (ISPR) using data from the 2010 Global Adult Tobacco Survey in China. Results The prevalence rate of current smoking was 40.6% in our sample, and 57.5% in males and 6.3% in females. The ISPRs of all patients, men and women were 1.11(95%CI: 0.95∼1.29), 1.07(95%CI = 0.91∼1.24) and 4.64(95%CI = 2.12∼8.82), respectively. The overall and male-specific prevalence of current smoking did not differ significantly between patients and the general population. In multiple logistic regression analysis, male sex, older age, poor marital status, alcohol use, use of first-generation antipsychotics, longer duration of illness, more frequent hospitalizations, and more severe negative symptoms were independently associated with current smoking. Conclusion Male Chinese inpatients with schizophrenia who received a mono-therapy of antipsychotics were not more likely to smoke than the general population. Cigarette smoking is more common in schizophrenia patients with more severe illness. PMID:24520390

  6. Two cases of malignant lymphoma with reactivation of resolved hepatitis B virus infection after bendamustine hydrochloride monotherapy.

    PubMed

    Hiraki, Yoshiki; Kawano, Akira; Shigematsu, Hirohisa; Miki, Koichiro; Nomura, Hideyuki; Shimoda, Shinji

    2016-09-01

    A 63-year-old female and a 63-year-old male with resolved HBV infection suffered a relapse of malignant lymphoma. After bendamustine hydrochloride monotherapy, HBV reactivation occurred. Entecavir treatment was commenced immediately, with tests for HBV DNA negative without development of hepatitis. Regular monitoring of HBV DNA based on the guidelines from the Japan Society of Hepatology was useful. PMID:27593368

  7. Fluoxetine Monotherapy in Attention-Deficit/Hyperactivity Disorder and Comorbid Non-Bipolar Mood Disorders in Children and Adolescents

    ERIC Educational Resources Information Center

    Quintana, Humberto; Butterbaugh, Grant J.; Purnell, William; Layman, Ann K.

    2007-01-01

    Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for developing comorbid non-bipolar mood disorders. Fluoxetine monotherapy is an established treatment for pediatric mood disorders; however its efficacy in ADHD and comorbid mood disorder is unknown. Therefore, we evaluated 30 children who met DSM-IV criteria for…

  8. Boosted protease inhibitor monotherapy in HIV-infected adults: outputs from a pan-European expert panel meeting

    PubMed Central

    2013-01-01

    While the introduction of combination highly active antiretroviral therapy (HAART) regimens represents an important advance in the management of human immunodeficiency virus (HIV)-infected patients, tolerability can be an issue and the use of several different agents may produce problems. The switch of combination HAART to ritonavir-boosted protease inhibitor (PI) monotherapy may offer the opportunity to maintain antiviral efficacy while reducing treatment complexity and the risks of toxicity. Current European AIDS Clinical Society (EACS) guidelines recognise ritonavir-boosted PI monotherapy with twice-daily lopinavir/ritonavir or once-daily darunavir/ritonavir as a possible option in patients who have intolerance to nucleoside reverse transcriptase inhibitors, or for treatment simplification. Clinical trials data for PI boosted monotherapy are encouraging, showing substantial efficacy in the majority of patients; however, further data are required before this approach can be recommended as a routine treatment. Available data indicate that the most suitable candidates for the use of boosted PI monotherapy are long-term virologically suppressed patients who have demonstrated good adherence to antiretroviral therapy, who do not have chronic hepatitis B, have no history of treatment failure on PIs and are able to tolerate low-dose ritonavir. PMID:23347595

  9. Photochemical internalization of tamoxifens transported by a "Trojan-horse" nanoconjugate into breast-cancer cell lines.

    PubMed

    Theodossiou, Theodossis A; Gonçalves, A Ricardo; Yannakopoulou, Konstantina; Skarpen, Ellen; Berg, Kristian

    2015-04-13

    Photochemical internalization (PCI) has shown great promise as a therapeutic alternative for targeted drug delivery by light-harnessed activation. However, it has only been applicable to therapeutic macromolecules or medium-sized molecules. Herein we describe the use of an amphiphilic, water-soluble porphyrin-β-cyclodextrin conjugate (mTHPP-βCD) as a "Trojan horse" to facilitate the endocytosis of CD-guest tamoxifens into breast-cancer cells. Upon irradiation, the porphyrin core of mTHPP-βCD expedited endosomal membrane rupture and tamoxifen release into the cytosol, as documented by confocal microscopy. The sustained complexation of mTHPP-βCD with tamoxifen was corroborated by 2D NMR spectroscopy and FRET studies. Following the application of PCI protocols with 4-hydroxytamoxifen (4-OHT), estrogen-receptor β-positive (Erβ+, but not ERβ-) cell groups exhibited extensive cytotoxicity and/or growth suspension even at 72 h after irradiation. PMID:25663536

  10. Studies on tamoxifen encapsulated in lipid vesicles: effect on the growth of human breast cancer MCF-7 cells.

    PubMed

    Bhatia, Amit; Bhushan, Shashi; Singh, Bhupinder; Katare, Om Prakash

    2009-01-01

    Tamoxifen is a nonsteroidal estrogen-receptor modulator widely used in the treatment of breast cancer. Apoptosis has been reported to be a major mechanism for its antitumor effect. In the current studies, an endeavor was made to investigate the efficacy of vesicularly encapsulated tamoxifen on human breast cancer MCF-7 cells. Phospholipid-based vesicular systems viz. conventional liposomes and elastic-membrane liposomes were employed to encapsulate the drug. The MTT colorimetric assay was used to determine the efficacy of the tested formulations. The results demonstrated composition-dependent strong inhibition in the viability of MCF-7 cells with encapsulated tamoxifen vis-à-vis free drug. The encouraging findings from the current work construe immense potential of the lipid-based vesicular systems in the treatment of breast cancer.

  11. [Adjuvant drug therapies for breast cancer].

    PubMed

    Huovinen, Riikka; Auvinen, Päivi; Mattson, Johanna; Joensuu, Heikki

    2015-01-01

    Most breast cancers are hormone receptor positive and exhibit a slow growth pattern. Based on biological properties, breast cancers are divided into four different biological subtypes. Furthermore, these subtypes are indicative of the risk of recurrence, which is also influenced by the size of the tumor and extension to lymph nodes. Postoperative adjuvant drug therapy is chosen on the basis of the biological type. Chemotherapy can be used in all subtypes. Hormonal therapies are used exclusively for the treatment of hormone receptor positive breast cancer. Trastuzumab antibody belongs to the treatment of the HER2 positive subtype. PMID:26245052

  12. Comparative effectiveness of biologic monotherapy versus combination therapy for patients with psoriatic arthritis: results from the Corrona registry

    PubMed Central

    Mease, Philip J; Collier, David H; Saunders, Katherine C; Li, Guo; Kremer, Joel M; Greenberg, Jeffrey D

    2015-01-01

    Objectives To characterise the comparative effectiveness of combination therapy (a tumour necrosis factor inhibitor (TNFi) and a conventional synthetic disease-modifying antirheumatic drug (csDMARD) such as methotrexate) and monotherapy (TNFi only) for psoriatic arthritis (PsA) from a large US registry. Methods The analysis included adult patients with PsA who were enrolled in the Corrona database (ClinicalTrials.gov, NCT01402661), had initiated a TNFi, were biologic naïve, and had a follow-up visit ≥90 days after drug initiation. The endpoints of the analysis were TNFi persistence (drug survival) and time to Clinical Disease Activity Index (CDAI) remission. All analyses were performed using propensity scoring, which were estimated using CDAI and patient sex, to control for channelling bias. Results Of 519 patients meeting the inclusion criteria (318 with combination therapy and 201 with monotherapy), the analysis population was 497 for TNFi persistence and 380 for time to remission. The difference between combination therapy (TNFi+methotrexate, 91% of patients; TNFi+other csDMARD, 9%) and monotherapy was not statistically significant for TNFi persistence (32 and 31 months, p=0.73) and time to remission (21 and 25 months, p=0.56). Predictors of TNFi persistence included Hispanic ethnicity (longer persistence), PsA duration (longer persistence), history of methotrexate use (shorter persistence), body mass index (shorter persistence) and disease activity (shorter persistence). Conclusions Patients with PsA from a large US registry experienced similar TNFi persistence on combination therapy and monotherapy. Prospective, randomised clinical trials evaluating the efficacy of combination therapy versus monotherapy would provide much-needed clarity on treatment options for patients with PsA. Trial registration number NCT01402661. PMID:26819748

  13. Polyionic vaccine adjuvants: another look at aluminum salts and polyelectrolytes

    PubMed Central

    2015-01-01

    Adjuvants improve the adaptive immune response to a vaccine antigen by modulating innate immunity or facilitating transport and presentation. The selection of an appropriate adjuvant has become vital as new vaccines trend toward narrower composition, expanded application, and improved safety. Functionally, adjuvants act directly or indirectly on antigen presenting cells (APCs) including dendritic cells (DCs) and are perceived as having molecular patterns associated either with pathogen invasion or endogenous cell damage (known as pathogen associated molecular patterns [PAMPs] and damage associated molecular patterns [DAMPs]), thereby initiating sensing and response pathways. PAMP-type adjuvants are ligands for toll-like receptors (TLRs) and can directly affect DCs to alter the strength, potency, speed, duration, bias, breadth, and scope of adaptive immunity. DAMP-type adjuvants signal via proinflammatory pathways and promote immune cell infiltration, antigen presentation, and effector cell maturation. This class of adjuvants includes mineral salts, oil emulsions, nanoparticles, and polyelectrolytes and comprises colloids and molecular assemblies exhibiting complex, heterogeneous structures. Today innovation in adjuvant technology is driven by rapidly expanding knowledge in immunology, cross-fertilization from other areas including systems biology and materials sciences, and regulatory requirements for quality, safety, efficacy and understanding as part of the vaccine product. Standardizations will aid efforts to better define and compare the structure, function and safety of adjuvants. This article briefly surveys the genesis of adjuvant technology and then re-examines polyionic macromolecules and polyelectrolyte materials, adjuvants currently not known to employ TLR. Specific updates are provided for aluminum-based formulations and polyelectrolytes as examples of improvements to the oldest and emerging classes of vaccine adjuvants in use. PMID:25648619

  14. In Vivo Performance and Properties of Tamoxifen Metabolites for CreERT2 Control

    PubMed Central

    Dolbois, Aymeric; Blazkova, Kristyna; Hess, Christopher; Low, Larry W. L.; Burger, Sibylle; Samson, Natasha; Carney, Tom J.; Bartunek, Petr; Nevado, Cristina

    2016-01-01

    Mutant Estrogen Receptor (ERT2) ligand-binding domain fusions with Cre recombinase are a key tool for spatio-temporally controlled genetic recombination with the Cre/lox system. CreERT2 is efficiently activated in a concentration-dependent manner by the Tamoxifen metabolite trans-4-OH-Tamoxifen (trans-4-OHT). Reproducible and efficient Cre/lox experimentation is hindered by the gradual loss of CreERT2 induction potency upon prolonged storage of dissolved trans-4-OHT, which potentially results from gradual trans-to-cis isomerization or degradation. Here, we combined zebrafish CreERT2 recombination experiments and cell culture assays to document the gradual activity loss of trans-4-OHT and describe the alternative Tamoxifen metabolite Endoxifen as more stable alternative compound. Endoxifen retains potent activation upon prolonged storage (3 months), yet consistently induces half the ERT2 domain fusion activity compared to fresh trans-4-OHT. Using 1H-NMR analysis, we reveal that trans-4-OHT isomerization is undetectable upon prolonged storage in either DMSO or Ethanol, ruling out isomer transformation as cause for the gradual loss of trans-4-OHT activity. We further establish that both trans-4-OHT and Endoxifen are insensitive to light exposure under regular laboratory handling conditions. We attribute the gradual loss of trans-4-OHT potency to precipitation over time, and show that heating of aged trans-4-OHT aliquots reinstates their CreERT2 induction potential. Our data establish Endoxifen as potent and reproducible complementary compound to 4-OHT to control ERT2 domain fusion proteins in vivo, and provide a framework for efficient chemically controlled recombination experiments. PMID:27077909

  15. In Vivo Performance and Properties of Tamoxifen Metabolites for CreERT2 Control.

    PubMed

    Felker, Anastasia; Nieuwenhuize, Susan; Dolbois, Aymeric; Blazkova, Kristyna; Hess, Christopher; Low, Larry W L; Burger, Sibylle; Samson, Natasha; Carney, Tom J; Bartunek, Petr; Nevado, Cristina; Mosimann, Christian

    2016-01-01

    Mutant Estrogen Receptor (ERT2) ligand-binding domain fusions with Cre recombinase are a key tool for spatio-temporally controlled genetic recombination with the Cre/lox system. CreERT2 is efficiently activated in a concentration-dependent manner by the Tamoxifen metabolite trans-4-OH-Tamoxifen (trans-4-OHT). Reproducible and efficient Cre/lox experimentation is hindered by the gradual loss of CreERT2 induction potency upon prolonged storage of dissolved trans-4-OHT, which potentially results from gradual trans-to-cis isomerization or degradation. Here, we combined zebrafish CreERT2 recombination experiments and cell culture assays to document the gradual activity loss of trans-4-OHT and describe the alternative Tamoxifen metabolite Endoxifen as more stable alternative compound. Endoxifen retains potent activation upon prolonged storage (3 months), yet consistently induces half the ERT2 domain fusion activity compared to fresh trans-4-OHT. Using 1H-NMR analysis, we reveal that trans-4-OHT isomerization is undetectable upon prolonged storage in either DMSO or Ethanol, ruling out isomer transformation as cause for the gradual loss of trans-4-OHT activity. We further establish that both trans-4-OHT and Endoxifen are insensitive to light exposure under regular laboratory handling conditions. We attribute the gradual loss of trans-4-OHT potency to precipitation over time, and show that heating of aged trans-4-OHT aliquots reinstates their CreERT2 induction potential. Our data establish Endoxifen as potent and reproducible complementary compound to 4-OHT to control ERT2 domain fusion proteins in vivo, and provide a framework for efficient chemically controlled recombination experiments. PMID:27077909

  16. In Vivo Performance and Properties of Tamoxifen Metabolites for CreERT2 Control.

    PubMed

    Felker, Anastasia; Nieuwenhuize, Susan; Dolbois, Aymeric; Blazkova, Kristyna; Hess, Christopher; Low, Larry W L; Burger, Sibylle; Samson, Natasha; Carney, Tom J; Bartunek, Petr; Nevado, Cristina; Mosimann, Christian

    2016-01-01

    Mutant Estrogen Receptor (ERT2) ligand-binding domain fusions with Cre recombinase are a key tool for spatio-temporally controlled genetic recombination with the Cre/lox system. CreERT2 is efficiently activated in a concentration-dependent manner by the Tamoxifen metabolite trans-4-OH-Tamoxifen (trans-4-OHT). Reproducible and efficient Cre/lox experimentation is hindered by the gradual loss of CreERT2 induction potency upon prolonged storage of dissolved trans-4-OHT, which potentially results from gradual trans-to-cis isomerization or degradation. Here, we combined zebrafish CreERT2 recombination experiments and cell culture assays to document the gradual activity loss of trans-4-OHT and describe the alternative Tamoxifen metabolite Endoxifen as more stable alternative compound. Endoxifen retains potent activation upon prolonged storage (3 months), yet consistently induces half the ERT2 domain fusion activity compared to fresh trans-4-OHT. Using 1H-NMR analysis, we reveal that trans-4-OHT isomerization is undetectable upon prolonged storage in either DMSO or Ethanol, ruling out isomer transformation as cause for the gradual loss of trans-4-OHT activity. We further establish that both trans-4-OHT and Endoxifen are insensitive to light exposure under regular laboratory handling conditions. We attribute the gradual loss of trans-4-OHT potency to precipitation over time, and show that heating of aged trans-4-OHT aliquots reinstates their CreERT2 induction potential. Our data establish Endoxifen as potent and reproducible complementary compound to 4-OHT to control ERT2 domain fusion proteins in vivo, and provide a framework for efficient chemically controlled recombination experiments.

  17. Prepubertal tamoxifen treatment affects development of heifer reproductive tissues and related signaling pathways.

    PubMed

    Al Naib, A; Tucker, H L M; Xie, G; Keisler, D H; Bartol, F F; Rhoads, R P; Akers, R M; Rhoads, M L

    2016-07-01

    Prepubertal exposure of the developing ovaries and reproductive tract (RT) to estrogen or xenoestrogens can have acute and long-term consequences that compromise the reproductive performance of cattle. This research examined effects of the selective estrogen receptor modulator tamoxifen (TAM) on gene and protein abundance in prepubertal ovaries and RT, with a particular focus on signaling pathways that affect morphology. Tamoxifen was administered to Holstein heifer calves (n=8) daily (0.3mg/kg subcutaneously) from 28 to 120 d of age, when tissues were collected. Control calves (n=7) received an equal volume of excipient. Weight, gross measurements, and samples of reproductive tissues were collected, and protein and mRNA were extracted from snap-frozen samples of vagina, cervix, uterus, oviduct, ovary, and liver. Neither estradiol nor insulin-like growth factor I (IGFI) concentrations in the serum were affected by TAM treatment. Tamoxifen treatment reduced ovarian weight independently from effects on antral follicle populations, as there was no difference in visible antral follicle numbers on the day of collection. Estrogen receptor α (ESR1) and β (ESR2) mRNA, ESR1 protein, IGFI, progesterone receptor, total growth hormone receptor, WNT4, WNT5A, and WNT7A mRNA, in addition to mitogen-activated protein kinase (MAPK) and phosphorylated MAPK proteins were affected differently depending on the tissue examined. However, neither IGFI receptor mRNA nor protein abundance were affected by TAM treatment. Results indicate that reproductive development in prepubertal Holstein heifer calves is TAM-sensitive, and that bovine RT and ovarian development are supported, in part, by estrogen receptor-dependent mechanisms during the period studied here. Potential long-term consequences of such developmental disruption remain to be defined. PMID:27085397

  18. Endometrial pathology in postmenopausal tamoxifen treatment: comparison between gynaecologically symptomatic and asymptomatic breast cancer patients.

    PubMed Central

    Cohen, I; Perel, E; Flex, D; Tepper, R; Altaras, M M; Cordoba, M; Beyth, Y

    1999-01-01

    AIMS: To evaluate whether endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic rather than in gynaecologically asymptomatic postmenopausal breast cancer patients with tamoxifen treatment; and to evaluate the possible influence of various clinical factors on the incidence of endometrial pathology. METHODS: Endometrial histological findings, transvaginal ultrasonographic endometrial thickness, demographic characteristics, health habits, and risk factors for endometrial cancer were compared between 14 gynaecologically symptomatic (group I) and 224 gynaecologically asymptomatic (group II) postmenopausal breast cancer patients with tamoxifen treatment. RESULTS: Overall, 28.6% of the study population had endometrial pathology. The incidence of overall positive endometrial histological findings was significantly higher in group I than in group II (92.9% v 24.6%, p < 0.0001). Atrophic endometrium was more common in group II than in group I (75.3% v 7.1%, p < 0.0001). Most other endometrial pathology was significantly more common in group I than in group II (endometrial hyperplasia, 35.7% v 5.6%, p < 0.0001; endometrial polyps, 35.7% v 13.4%, p < 0.0111; endometrial carcinoma, 21.5% v 0.9%, p < 0.0001). Endometrial pathology appeared considerably later in the gynaecologically asymptomatic patients than in gynaecologically symptomatic patients (p = 0.0002). Vaginal bleeding or spotting occurred exclusively in group I. The incidence of endometrial pathology in the entire study population was consistent with that reported elsewhere, and higher than that reported for healthy postmenopausal women. CONCLUSIONS: Endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic postmenopausal breast cancer patients with tamoxifen treatment, and after a shorter duration of time, than in gynaecologically asymptomatic patients. PMID:10474520

  19. Synthesis of the E and Z isomers of the antiestrogen tamoxifen and its metabolite, hydroxytamoxifen, in tritium-labeled form

    SciTech Connect

    Robertson, D.W.; Katzenellenbogen, J.A.

    1982-06-04

    Both isomers of the potent antiestrogen tamoxifen (1,2-diphenyl-1-(4-(2-(dimethylamino)ethoxy)phenyl)-1-butene: E isomer = ICI-47699; Z isomer = ICI-46474, Nolvadex) and its metabolite, hydroxytamoxifen (1-(4-(2-(dimethylamino)ethoxy)phenyl)-1-(4-hydroxyphenyl)-2-phenyl-1-butene), have been synthesized in a high specific activity, tritium-labeled form by catalytic tritium-halogen exchange performed on brominated precursors. The synthesis of another precursor to labeled tamoxifen which would enable the incorporation of three tritium atoms into the molecule by tritium-halogen exchange is reported.

  20. Effect of different lipids and surfactants on formulation of solid lipid nanoparticles incorporating tamoxifen citrate.

    PubMed

    Upadhyay, S U; Patel, J K; Patel, V A; Saluja, A K

    2012-03-01

    Tamoxifen Citrate (TC) is an estrogen receptor antagonist and drug of choice for hormone sensitive breast cancer. Solid Lipid Nanoparticles loaded with TC were prepared by High Shear Homogenization followed by Ultrasonication. The aim of the present work is to study the effect of four different Solid Lipids and three Surfactants on Formulation and Stability of SLN. They were characterized for Particle size, Polydispersity Index and Zeta Potential by Zetasizer Nano. SLN prepared by Solid Lipid Compritol 888 (Glyceryldibehenate) and Tween 80 (1%) showed desired Particle Size of 206.9 nm, PDI of 0.046 and Zeta Potential of 9.32 mV. PMID:23066183

  1. The mode of action of immunological adjuvants.

    PubMed

    Allison, A C

    1998-01-01

    Adjuvants augment immune responses to antigens and influence the balance between cell-mediated and humoral responses, as well as the isotypes of antibodies formed. New adjuvant formulations include antigen-carrying vehicles and small molecules with immunomodulating activity. Widely used two-phase vehicles comprise liposomes and microfluidized squalene or squalane emulsions. These are believed to target antigens to antigen-presenting cells, including dendritic cells (DC), follicular dendritic cells (FDC) and B-lymphocytes. Activation of complement generates C3d, which binds CR2 (CD21) on FDC and B-lymphocytes, thereby stimulating the proliferation of the latter and the generation of B-memory. Targeting of antigens to DC may favour cell-mediated immunity. Immunomodulating agents induce the production of cytokine cascades. In a primary cascade at injection sites TNF-alpha, GM-CSF and IL-1 are produced. TNF-alpha promotes migration of DC to lymphoid tissues, while GM-CSF and IL-1 accelerate the maturation of DC into efficient antigen-presenting cells for T-lymphocytes. In a secondary cytokine cascade in draining lymph nodes, DC produce IL-12, which induces Th1 responses with the production of IFN-gamma. The cytokines elicit cell-mediated immune responses and the formation of antibodies of protective isotypes, such as IgG2a in the mouse and IgG1 in humans. Antibodies of these isotypes activate complement and collaborate with antibody-dependent effector cells in protective immune responses.

  2. Assessing the safety of adjuvanted vaccines.

    PubMed

    Ahmed, S Sohail; Plotkin, Stanley A; Black, Steven; Coffman, Robert L

    2011-07-27

    Despite the very low risk-to-benefit ratio of vaccines, fear of negative side effects has discouraged many people from getting vaccinated, resulting in reemergence of previously controlled diseases such as measles, pertussis, and diphtheria. Part of this fear stems from the lack of public awareness of the many preclinical and clinical safety evaluations that vaccines must undergo before they are available to the general public, as well as from misperceptions of what adjuvants are or why they are used in vaccines. The resultant "black box" leads to a preoccupation with rare side effects (such as autoimmune diseases) that are speculated, but not proven, to be linked to some vaccinations. The focus of this review article is to open this black box and provide a conceptual framework for how vaccine safety is traditionally assessed. We discuss the strengths and shortcomings of tools that can be and are used preclinically (in animal studies), translationally (in biomarker studies with human sera or cells), statistically (for disease epidemiology), and clinically (in the design of human trials) to help ascertain the risk of the infrequent and delayed adverse events that arise in relation to adjuvanted vaccine administration.

  3. Neoadjuvant and Adjuvant Chemotherapy of Cervical Cancer.

    PubMed

    Mallmann, Peter; Mallmann, Christoph

    2016-01-01

    Neoadjuvant chemotherapy is indicated in patients who can tolerate the side effects of a chemotherapy and with preoperative presentation of one of the following clinical risk situations: bulky disease with a maximal tumor diameter of > 4 cm, suspicious lymph nodes in magnetic resonance imaging (MRI), computed tomography (CT) scan or endosonography, histopathologically confirmed lymph node metastasis, or histopathologically documented risk factors such as G3 and L1V1. A neoadjuvant chemotherapy followed by surgery should be performed with cisplatin at a dosage of > 25 mg/m2 per week and an application interval of < 14 days. The previously published data suggests an improved rate of complete resection and reduced incidences of positive lymph nodes and parametric infiltration. Accordingly, the percentage of patients in need for adjuvant radiochemotherapy after operation can be significantly reduced. Some studies demonstrated a prolongation of progression-free and overall survival. Following the previously published studies, adjuvant chemotherapy after operation or after radiochemotherapy has no significant effect on the overall survival and, following the current guidelines, should be avoided. PMID:27614740

  4. Safety assessment of adjuvanted vaccines: Methodological considerations.

    PubMed

    Tavares Da Silva, Fernanda; Di Pasquale, Alberta; Yarzabal, Juan P; Garçon, Nathalie

    2015-01-01

    Adjuvants mainly interact with the innate immune response and are used to enhance the quantity and quality of the downstream adaptive immune response to vaccine antigens. Establishing the safety of a new adjuvant-antigen combination is achieved through rigorous evaluation that begins in the laboratory, and that continues throughout the vaccine life-cycle. The strategy for the evaluation of safety pre-licensure is guided by the disease profile, vaccine indication, and target population, and it is also influenced by available regulatory guidelines. In order to allow meaningful interpretation of clinical data, clinical program methodology should be optimized and standardized, making best use of all available data sources. Post-licensure safety activities are directed by field experience accumulated pre- and post-licensure clinical trial data and spontaneous adverse event reports. Continued evolution of safety evaluation processes that keep pace with advances in vaccine technology and updated communication of the benefit-risk profile is necessary to maintain public confidence in vaccines.

  5. The mode of action of immunological adjuvants.

    PubMed

    Allison, A C

    1998-01-01

    Adjuvants augment immune responses to antigens and influence the balance between cell-mediated and humoral responses, as well as the isotypes of antibodies formed. New adjuvant formulations include antigen-carrying vehicles and small molecules with immunomodulating activity. Widely used two-phase vehicles comprise liposomes and microfluidized squalene or squalane emulsions. These are believed to target antigens to antigen-presenting cells, including dendritic cells (DC), follicular dendritic cells (FDC) and B-lymphocytes. Activation of complement generates C3d, which binds CR2 (CD21) on FDC and B-lymphocytes, thereby stimulating the proliferation of the latter and the generation of B-memory. Targeting of antigens to DC may favour cell-mediated immunity. Immunomodulating agents induce the production of cytokine cascades. In a primary cascade at injection sites TNF-alpha, GM-CSF and IL-1 are produced. TNF-alpha promotes migration of DC to lymphoid tissues, while GM-CSF and IL-1 accelerate the maturation of DC into efficient antigen-presenting cells for T-lymphocytes. In a secondary cytokine cascade in draining lymph nodes, DC produce IL-12, which induces Th1 responses with the production of IFN-gamma. The cytokines elicit cell-mediated immune responses and the formation of antibodies of protective isotypes, such as IgG2a in the mouse and IgG1 in humans. Antibodies of these isotypes activate complement and collaborate with antibody-dependent effector cells in protective immune responses. PMID:9554254

  6. Safety assessment of adjuvanted vaccines: Methodological considerations

    PubMed Central

    Da Silva, Fernanda Tavares; Di Pasquale, Alberta; Yarzabal, Juan P; Garçon, Nathalie

    2015-01-01

    Adjuvants mainly interact with the innate immune response and are used to enhance the quantity and quality of the downstream adaptive immune response to vaccine antigens. Establishing the safety of a new adjuvant-antigen combination is achieved through rigorous evaluation that begins in the laboratory, and that continues throughout the vaccine life-cycle. The strategy for the evaluation of safety pre-licensure is guided by the disease profile, vaccine indication, and target population, and it is also influenced by available regulatory guidelines. In order to allow meaningful interpretation of clinical data, clinical program methodology should be optimized and standardized, making best use of all available data sources. Post-licensure safety activities are directed by field experience accumulated pre- and post-licensure clinical trial data and spontaneous adverse event reports. Continued evolution of safety evaluation processes that keep pace with advances in vaccine technology and updated communication of the benefit-risk profile is necessary to maintain public confidence in vaccines. PMID:26029975

  7. Adjuvant chemotherapy for soft tissue sarcoma.

    PubMed

    Casali, Paolo G

    2015-01-01

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

  8. CpG oligodeoxynucleotides as mucosal adjuvants

    PubMed Central

    Iho, Sumiko; Maeyama, Jun-ichi; Suzuki, Fumiko

    2015-01-01

    Bacterial DNA comprising palindromic sequences and containing unmethylated CpG is recognized by toll-like receptor 9 of plasmacytoid dendritic cells (pDCs) and induces the production of interferon-α and chemokines, leading to the activation of a Th1 immune response. Therefore, synthetic equivalents of bacterial DNA (CpG oligodeoxynucleotides) have been developed for clinical applications. They are usually phosphorothioated for in vivo use; this approach also leads to adverse effects as reported in mouse models.Mucosal vaccines that induce both mucosal and systemic immunity received substantial attention in recent years. For their development, phosphodiester-linked oligodeoxynucleotides, including the sequence of a palindromic CpG DNA may be advantageous as adjuvants because their target pDCs are present right there, in the mucosa of the vaccination site. In addition, the probability of adverse effects is believed to be low. Here, we review the discovery of such CpG oligodeoxynucleotides and their possible use as mucosal adjuvants. PMID:25751765

  9. Evaluating spray adjuvants to extend residual activity of microbiol pesticides`

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Based on requests to improve the residual efficacy of baculovirus applications, a commercial adjuvant (Nu-Film 17(R) and an experimental lignin adjuvant were evaluated for resistance to environmental degradation. Nu-Film is a commercial product derived from pine resin; and lignin is a by-product of...

  10. Vaccine Adjuvants: from 1920 to 2015 and Beyond

    PubMed Central

    Di Pasquale, Alberta; Preiss, Scott; Tavares Da Silva, Fernanda; Garçon, Nathalie

    2015-01-01

    The concept of stimulating the body’s immune response is the basis underlying vaccination. Vaccines act by initiating the innate immune response and activating antigen presenting cells (APCs), thereby inducing a protective adaptive immune response to a pathogen antigen. Adjuvants are substances added to vaccines to enhance the immunogenicity of highly purified antigens that have insufficient immunostimulatory capabilities, and have been used in human vaccines for more than 90 years. While early adjuvants (aluminum, oil-in-water emulsions) were used empirically, rapidly increasing knowledge on how the immune system interacts with pathogens means that there is increased understanding of the role of adjuvants and how the formulation of modern vaccines can be better tailored towards the desired clinical benefit. Continuing safety evaluation of licensed vaccines containing adjuvants/adjuvant systems suggests that their individual benefit-risk profile remains favorable. Adjuvants contribute to the initiation of the innate immune response induced by antigens; exemplified by inflammatory responses at the injection site, with mostly localized and short-lived effects. Activated effectors (such as APCs) then move to draining lymph nodes where they direct the type, magnitude and quality of the adaptive immune response. Thus, the right match of antigens and adjuvants can potentiate downstream adaptive immune responses, enabling the development of new efficacious vaccines. Many infectious diseases of worldwide significance are not currently preventable by vaccination. Adjuvants are the most advanced new technology in the search for new vaccines against challenging pathogens and for vulnerable populations that respond poorly to traditional vaccines. PMID:26343190

  11. Update on Adjuvant Chemotherapy for Early Breast Cancer

    PubMed Central

    Rampurwala, Murtuza M; Rocque, Gabrielle B; Burkard, Mark E

    2014-01-01

    Breast cancer is the second most common cancer in women worldwide. Although most women are diagnosed with early breast cancer, a substantial number recur due to persistent micro-metastatic disease. Systemic adjuvant chemotherapy improves outcomes and has advanced from first-generation regimens to modern dose-dense combinations. Although chemotherapy is the cornerstone of adjuvant therapy, new biomarkers are identifying patients who can forego such treatment. Neo-adjuvant therapy is a promising platform for drug development, but investigators should recognize the limitations of surrogate endpoints and clinical trials. Previous decades have focused on discovering, developing, and intensifying adjuvant chemotherapy. Future efforts should focus on customizing therapy and reducing chemotherapy for patients unlikely to benefit. In some cases, it may be possible to replace chemotherapy with treatments directed at specific genetic or molecular breast cancer subtypes. Yet, we anticipate that chemotherapy will remain a critical component of adjuvant therapy for years to come. PMID:25336961

  12. Adjuvants in micro- to nanoscale: current state and future direction.

    PubMed

    Gupta, Ankur; Das, Soumen; Schanen, Brian; Seal, Sudipta

    2016-01-01

    Adjuvants have been used in vaccines for over 70 years to promote long-lived and sterilizing immunity. Since then, various adjuvant systems were developed by combining nanotechnology with natural and/or synthetic immunomodulatory molecules. These systems are biocompatible, immunogenic, and possess higher antigen carrying capacity. This article showcases advancements made in the adjuvant systems formulations, their synthesis routes, and the improvement of these adjuvants have brought in response to combat against ongoing global health threats such as malaria, hepatitis C, universal influenza, and human immunodeficiency virus. This review also highlights the interaction of adjuvants with the delivery of antigens to cells and unfolds mechanism of actions. In addition, this review discusses the physicochemical factors responsible for the efficient interaction of nanoadjuvants with antigen receptors to develop more effective, less reactogenic, and multifunctional systems for the next generation vaccines.

  13. [Adjuvants--essential components of new generation vaccines].

    PubMed

    Dzierzbicka, Krystyna; Kołodziejczyk, Aleksander M

    2006-01-01

    Adjuvants are essential components of vaccines that augment an immunological reaction of organism. New vaccines based on recombinant proteins and DNA, are more save than traditional vaccines but they are less immunogenic. Therefore, there is an urgent need for the development of new, improved vaccine adjuvants. There are two classes of adjuvants: vaccine delivery systems (e.g. emulsions, microparticles, immune-stimulating complexes ISCOMs, liposomes) and immunostimulatory adjuvants (e.g. lipopolysaccharide, monophosphoryl lipid A, CpG DNA, or muramylpeptides). The discovery of more potent and safer adjuvants may allow to development better prophylactic and therapeutic vaccines against chronic infectious (e.g., HSV, HIV, HCV, HBV, HPV, or Helicobacter pylori) and noninfectious diseases as multiple sclerosis, insulin-dependent diabetes, rheumatoid arthritis, allergy and tumors (e.g., melanoma, breast, or colon cancer). PMID:17078510

  14. Vaxjo: A Web-Based Vaccine Adjuvant Database and Its Application for Analysis of Vaccine Adjuvants and Their Uses in Vaccine Development

    PubMed Central

    Sayers, Samantha; Ulysse, Guerlain; Xiang, Zuoshuang; He, Yongqun

    2012-01-01

    Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO) in the Web Ontology Language (OWL) format. PMID:22505817

  15. Ixabepilone as monotherapy or in combination for the treatment of advanced breast cancer

    PubMed Central

    Bertino, Erin M; Ramaswamy, Bhuvaneswari

    2010-01-01

    Advanced breast cancer represents a therapeutic challenge for oncologists. Chemotherapy with anthracyclines and taxanes has improved survival in this setting, but resistant and refractory disease is common. Ixabepilone, an epothilone, is a recently approved chemotherapeutic agent, both as a single agent and in combination with capecitabine, with efficacy in patients with resistant advanced disease. In this review, the distinctive properties of this drug are discussed, as well as the clinical evidence of efficacy. Ongoing clinical trials are exploring the role of ixabepilone in several clinical settings: neoadjuvant, adjuvant, and novel combinations. PMID:24367163

  16. Mechanism of Immunopotentiation and Safety of Aluminum Adjuvants

    PubMed Central

    HogenEsch, Harm

    2013-01-01

    Aluminum-containing adjuvants are widely used in preventive vaccines against infectious diseases and in preparations for allergy immunotherapy. The mechanism by which they enhance the immune response remains poorly understood. Aluminum adjuvants selectively stimulate a Th2 immune response upon injection of mice and a mixed response in human beings. They support activation of CD8 T cells, but these cells do not undergo terminal differentiation to cytotoxic T cells. Adsorption of antigens to aluminum adjuvants enhances the immune response by facilitating phagocytosis and slowing the diffusion of antigens from the injection site which allows time for inflammatory cells to accumulate. The adsorptive strength is important as high affinity interactions interfere with the immune response. Adsorption can also affect the physical and chemical stability of antigens. Aluminum adjuvants activate dendritic cells via direct and indirect mechanisms. Phagocytosis of aluminum adjuvants followed by disruption of the phagolysosome activates NLRP3-inflammasomes resulting in the release of active IL-1β and IL-18. Aluminum adjuvants also activate dendritic cells by binding to membrane lipid rafts. Injection of aluminum-adjuvanted vaccines causes the release of uric acid, DNA, and ATP from damaged cells which in turn activate dendritic cells. The use of aluminum adjuvant is limited by weak stimulation of cell-mediated immunity. This can be enhanced by addition of other immunomodulatory molecules. Adsorption of these molecules is determined by the same mechanisms that control adsorption of antigens and can affect the efficacy of such combination adjuvants. The widespread use of aluminum adjuvants can be attributed in part to the excellent safety record based on a 70-year history of use. They cause local inflammation at the injection site, but also reduce the severity of systemic and local reactions by binding biologically active molecules in vaccines. PMID:23335921

  17. Optimal management of combined dyslipidemia: what have we behind statins monotherapy?

    PubMed

    Tenenbaum, Alexander; Fisman, Enrique Z; Motro, Michael; Adler, Yehuda

    2008-01-01

    Evidence of the effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) within continuum of atherothrombotic conditions and particularly in the treatment and prevention of coronary heart disease (CHD) is well established. Large-scale, randomized, prospective trials involving patients with CHD have shown that statins reduce the clinical consequences of atherosclerosis, including cardiovascular deaths, nonfatal myocardial infarction and stroke, hospitalization for acute coronary syndrome and heart failure, as well as the need for coronary revascularization. Direct testing of varying degrees of low-density lipoprotein (LDL)- cholesterol lowering has now been carried out in 4 large outcomes trials: PROVE IT-TIMI 22, A to Z, TNT and IDEAL. However, the question whether more aggressive LDL-cholesterol lowering by high-dose statins monotherapy is an appropriate strategy is still open: higher doses of statins are more effective mainly for the prevention of the nonfatal cardiovascular events but such doses are associated with an increase in hepatotoxicity, myopathy and concerns regarding noncardiovascular death. Moreover, despite the increasing use of statins, a significant number of coronary events still occur and many such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is now being paid to combined atherogenic dyslipidemia which typically presented in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or 'lipid quartet') - hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol levels, a preponderance of small, dense LDL particles and an accumulation of cholesterol-rich remnant particles - emerged as the greatest 'competitor' of LDL-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP, HHS, VAHIT and FIELD) give further support to the hypothesis that patients with insulin

  18. Safety and Efficacy of Moxifloxacin Monotherapy for Treatment of Orthopedic Implant-Related Staphylococcal Infections ▿

    PubMed Central

    San Juan, Rafael; Garcia-Reyne, Ana; Caba, Pedro; Chaves, Fernando; Resines, Carlos; Llanos, Fernando; López-Medrano, Francisco; Lizasoain, Manuel; Aguado, Jose Maria

    2010-01-01

    The rifampin-ciprofloxacin combination is recommended for treatment of orthopedic implant-related staphylococcal infections to avoid the emergence of ciprofloxacin resistance; however, the efficacy of this combination is limited by the tolerability problems associated with the use of rifampin. Moxifloxacin is a quinolone up to 10 times more active against staphylococci than ciprofloxacin and the risk of resistance development during monotherapy against staphylococci is theoretically lower for moxifloxacin, but information regarding its use in bone infections is lacking. The aim of the present study was to evaluate the safety and clinical efficacy of moxifloxacin monotherapy in patients with orthopedic implant-related staphylococcal infections. From June 2006 to April 2009, all patients with culture-proven infection by quinolone-sensitive staphylococcal strains associated with orthopedic implants at our institution were included in a management protocol that mostly included specific surgery, 1 to 2 weeks of an intravenous course of cloxacillin-cefazolin or vancomycin, and long-term therapy with moxifloxacin (400 mg/day for 3 months). Cure was defined as (i) a lack of clinical signs and symptoms of infection, (ii) a C-reactive protein level less than 5 mg/liter, and (iii) absence of radiological signs of loosening or infection at the latest follow-up visit. Failure was defined as (i) persisting clinical and/or laboratory signs of infection or (ii) persisting or new isolation of the initial microorganism. A total of 48 patients with a median follow-up of 716 days (range, 102 to 1,613 days) were included in the study. Complete drug compliance was achieved in all but two patients (4.2%), who required drug discontinuation because of side effects (diarrhea and dizziness). No moxifloxacin-induced arrhythmia was reported. Twenty patients had joint prosthesis infections (5 acute-onset infections and 15 chronic infections), and 28 patients had osteosynthesis material

  19. Ethosuximide, Valproic Acid and Lamotrigine in Childhood Absence Epilepsy: Initial Monotherapy Outcomes at 12 months

    PubMed Central

    Glauser, Tracy A.; Cnaan, Avital; Shinnar, Shlomo; Hirtz, Deborah G.; Dlugos, Dennis; Masur, David; Clark, Peggy O.; Adamson, Peter C.

    2012-01-01

    Purpose Determine the optimal initial monotherapy for children with newly diagnosed childhood absence epilepsy based on 12 months of double blind therapy. Methods A double-blind, randomized controlled clinical trial compared the efficacy, tolerability and neuropsychological effects of ethosuximide, valproic acid and lamotrigine in children with newly diagnosed childhood absence epilepsy. Study medications were titrated to clinical response and subjects remained in the trial unless they reached a treatment failure criterion. Maximal target doses were ethosuximide 60 mg/kg/day or 2000 mg/day, valproic acid 60 mg/kg/day or 3000 mg/day and lamotrigine 12 mg/kg/day or 600 mg/day. Original primary outcome was at 16–20 weeks and included a video EEG assessment. For this report, the main effectiveness outcome was the freedom from failure rate 12 months after randomization and included a video EEG assessment; differential drug effects were determined by pairwise comparisons. The main cognitive outcome was the percentage of subjects experiencing attentional dysfunction at the Month 12 visit. Key Findings A total of 453 children were enrolled and randomized; seven were deemed ineligible and 446 subjects comprised the overall efficacy cohort. There were no demographic differences between the three cohorts. By 12 months after starting therapy, only 37% of all enrolled subjects were free from treatment failure on their first medication. At the Month 12 visit, the freedom-from-failure rates for ethosuximide and valproic acid were similar (45% and 44%, respectively; odds ratio with valproic acid vs. ethosuximide, 0.94; 95% confidence interval [CI], 0.60 to 1.48; P = 0.82) and were higher than the rate for lamotrigine (21%; odds ratio with ethosuximide vs. lamotrigine, 3.09; 95% CI, 1.86 to 5.13; odds ratio with valproic acid vs. lamotrigine, 2.90; 95% CI, 1.74 to 4.83; P<0.001 for both comparisons). The frequency of treatment failures due to lack of seizure control (p < 0

  20. In-vitro transcutaneous delivery of tamoxifen and gamma-linolenic acid from borage oil containing ethanol and 1,8-cineole.

    PubMed

    Ho, Suzanna; Calder, Richard J; Thomas, Christopher P; Heard, Charles M

    2004-11-01

    The objective of this study was to examine the effects of ethanol and 1,8-cineole on the transcutaneous delivery of tamoxifen and gamma-linolenic acid (GLA) as a two-pronged anti-breast cancer therapy. Formulations containing tamoxifen and varying concentrations of borage oil (approximately 25% GLA), 1,8-cineole and ethanol were prepared and the simultaneous permeation of tamoxifen and GLA determined across full-thickness pig skin using Franz-type diffusion cells over 48 h. Analysis of tamoxifen and GLA (as methyl ester) were by reverse-phase HPLC. The highest flux of tamoxifen of 488.2 +/- 191 x 10(-3) microg cm(-2) h(-1) was observed with a formulation containing 20% 1,8-cineole and 20% ethanol. The same formulation also provided the greatest flux of GLA, 830.6 x 10(-3) microg cm(-2 )h(-1). The findings from this work demonstrate the ability of 1,8-cineole and ethanol to enhance the in-vitro permeation of tamoxifen and GLA across the skin and support the plausibility of simultaneously delivering tamoxifen and GLA transcutaneously as a two-pronged anti-breast cancer system. PMID:15525441

  1. Effects of Aqueous Extracts of Chicory and Milk Thistle on Serum Concentrations of Copper, Zinc, and Manganese in Tamoxifen-Treated Rats.

    PubMed

    Abbasalipourkabir, Roghayeh; Ziamajidi, Nasrin; Nasiri, Abolfazl; Behrouj, Hamid

    2016-09-01

    Some medications may change trace element levels in the body. Extracts of various plants, due to having the several elements, can have beneficial effects. Consumption of herbal extracts with chemical drugs may reduce adverse effects of medication. The goal of this study was to evaluate copper (Cu), zinc (Zn), and manganese (Mn) concentrations in serum of rats treated with tamoxifen, chicory, and/or milk thistle extracts. Therefore, 36 adult female Wistar rats were divided into six groups: normal control, chicory control, milk thistle control, tamoxifen, tamoxifen-chicory, and tamoxifen-milk thistle. At the end of the study, the blood samples were collected and sera isolated by centrifugation and analyzed by the atomic absorption spectrophotometry for Cu, Zn, and Mn levels. The Zn concentration increased in milk thistle-supplemented groups. The Cu level increased in the chicory control group only. Tamoxifen had no affect on Cu, Zn, and Mn levels, but seed extract of milk thistle increased Zn concentration, and chicory root extract increased Cu concentration. Although elevated levels of Cu in rats receiving tamoxifen-chicory were milder than rats treated only with chicory, it seems that the extract and tamoxifen impact on the Cu are in conflict with each other. PMID:26875177

  2. Effects of Aqueous Extracts of Chicory and Milk Thistle on Serum Concentrations of Copper, Zinc, and Manganese in Tamoxifen-Treated Rats.

    PubMed

    Abbasalipourkabir, Roghayeh; Ziamajidi, Nasrin; Nasiri, Abolfazl; Behrouj, Hamid

    2016-09-01

    Some medications may change trace element levels in the body. Extracts of various plants, due to having the several elements, can have beneficial effects. Consumption of herbal extracts with chemical drugs may reduce adverse effects of medication. The goal of this study was to evaluate copper (Cu), zinc (Zn), and manganese (Mn) concentrations in serum of rats treated with tamoxifen, chicory, and/or milk thistle extracts. Therefore, 36 adult female Wistar rats were divided into six groups: normal control, chicory control, milk thistle control, tamoxifen, tamoxifen-chicory, and tamoxifen-milk thistle. At the end of the study, the blood samples were collected and sera isolated by centrifugation and analyzed by the atomic absorption spectrophotometry for Cu, Zn, and Mn levels. The Zn concentration increased in milk thistle-supplemented groups. The Cu level increased in the chicory control group only. Tamoxifen had no affect on Cu, Zn, and Mn levels, but seed extract of milk thistle increased Zn concentration, and chicory root extract increased Cu concentration. Although elevated levels of Cu in rats receiving tamoxifen-chicory were milder than rats treated only with chicory, it seems that the extract and tamoxifen impact on the Cu are in conflict with each other.

  3. In-vitro transcutaneous delivery of tamoxifen and gamma-linolenic acid from borage oil containing ethanol and 1,8-cineole.

    PubMed

    Ho, Suzanna; Calder, Richard J; Thomas, Christopher P; Heard, Charles M

    2004-11-01

    The objective of this study was to examine the effects of ethanol and 1,8-cineole on the transcutaneous delivery of tamoxifen and gamma-linolenic acid (GLA) as a two-pronged anti-breast cancer therapy. Formulations containing tamoxifen and varying concentrations of borage oil (approximately 25% GLA), 1,8-cineole and ethanol were prepared and the simultaneous permeation of tamoxifen and GLA determined across full-thickness pig skin using Franz-type diffusion cells over 48 h. Analysis of tamoxifen and GLA (as methyl ester) were by reverse-phase HPLC. The highest flux of tamoxifen of 488.2 +/- 191 x 10(-3) microg cm(-2) h(-1) was observed with a formulation containing 20% 1,8-cineole and 20% ethanol. The same formulation also provided the greatest flux of GLA, 830.6 x 10(-3) microg cm(-2 )h(-1). The findings from this work demonstrate the ability of 1,8-cineole and ethanol to enhance the in-vitro permeation of tamoxifen and GLA across the skin and support the plausibility of simultaneously delivering tamoxifen and GLA transcutaneously as a two-pronged anti-breast cancer system.

  4. Advax-adjuvanted recombinant protective antigen provides protection against inhalational anthrax that is further enhanced by addition of murabutide adjuvant.

    PubMed

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

    2014-04-01

    Subunit vaccines against anthrax based on recombinant protective antigen (PA) potentially offer more consistent and less reactogenic anthrax vaccines but require adjuvants to achieve optimal immunogenicity. This study sought to determine in a murine model of pulmonary anthrax infection whether the polysaccharide adjuvant Advax or the innate immune adjuvant murabutide alone or together could enhance PA immunogenicity by comparison to an alum adjuvant. A single immunization with PA plus Advax adjuvant afforded significantly greater protection against aerosolized Bacillus anthracis Sterne strain 7702 than three immunizations with PA alone. Murabutide had a weaker adjuvant effect than Advax when used alone, but when murabutide was formulated together with Advax, an additive effect on immunogenicity and protection was observed, with complete protection after just two doses. The combined adjuvant formulation stimulated a robust, long-lasting B-cell memory response that protected mice against an aerosol challenge 18 months postimmunization with acceleration of the kinetics of the anamnestic IgG response to B. anthracis as reflected by ∼4-fold-higher anti-PA IgG titers by day 2 postchallenge versus mice that received PA with Alhydrogel. In addition, the combination of Advax plus murabutide induced approximately 3-fold-less inflammation than Alhydrogel as measured by in vivo imaging of cathepsin cleavage resulting from injection of ProSense 750. Thus, the combination of Advax and murabutide provided enhanced protection against inhalational anthrax with reduced localized inflammation, making this a promising next-generation anthrax vaccine adjuvanting strategy.

  5. Monotherapy versus dual therapy for the initial treatment of hypertension (PATHWAY-1): a randomised double-blind controlled trial

    PubMed Central

    MacDonald, Thomas M; Williams, Bryan; Caulfield, Mark; Cruickshank, J Kennedy; McInnes, Gordon; Sever, Peter; Webb, David J; Mackenzie, Isla S; Salsbury, Jackie; Morant, Steve; Ford, Ian; Brown, Morris J

    2015-01-01

    Introduction Previous studies have suggested that more intensive initial therapy for hypertension results in better long-term blood pressure (BP) control. We test this hypothesis comparing initial monotherapy with dual therapy in the management of essential hypertension. Methods and analysis The study is a prospective, multicentre, double-blind, active-controlled trial in patients with essential hypertension. Around 50% of patients studied will be newly diagnosed and the others will be known hypertensives who previously received only monotherapy. The trial is divided into three phases as follows: Phase 1 (Week 0–Week 16): Randomised, parallel-group, masked assignation to either combination or monotherapy. Phase 2 (Week 17–Week 32): Open-label combination therapy. Phase 3 (Week 33–Week 52): Open-label combination therapy plus open-label add-on (if BP is above 140/90 mm Hg). Hierarchical primary end points are: a comparison of home BP (home systolic blood pressure (HSBP)) averaged over the duration of phase 1 and 2 in the combination versus monotherapy arms. If combination is superior in this analysis, then the averaged mean HSBP between initial monotherapy and initial combination therapy at the end of phase 2 will be compared. Secondary end points include: BP control at 1 year; the role of age, baseline renin, sodium status, plasma volume, haemodynamic compensation and peripheral resistance on BP control; validation of the National Institute for Clinical Excellence/British Hypertension Society joint guideline algorithm; safety and tolerability of combination therapy; and the impact of combination versus monotherapy on left ventricular mass and aortic pulse wave velocity. A sample size of 536 (268 in each group) will have 90% power to detect a difference in means of 4 mm Hg. Ethics and dissemination PATHWAY 1 was approved by UK ethics (REC Reference 09/H0308/132). Trial results will be published and all participating subjects will be informed of the

  6. Monotherapy with Levetiracetam Versus Older AEDs: A Randomized Comparative Trial of Effects on Bone Health.

    PubMed

    Hakami, Tahir; O'Brien, Terence J; Petty, Sandra J; Sakellarides, Mary; Christie, Jemma; Kantor, Susan; Todaro, Marian; Gorelik, Alexandra; Seibel, Markus J; Yerra, Raju; Wark, John D

    2016-06-01

    Long-term anti-epileptic drug (AED) therapy is associated with increased fracture risk. This study tested whether substituting the newer AED levetiracetam has less adverse effects on bone than older AEDs. An open-label randomized comparative trial. Participants had "failed" initial monotherapy for partial epilepsy and were randomized to substitution monotherapy with levetiracetam or an older AED (carbamazepine or valproate sodium). Bone health assessments, performed at 3 and 15 months, included areal bone mineral density (aBMD) and content at lumbar spine (LS), total hip (TH), forearm (FA), and femoral neck (FN), radial and tibial peripheral quantitative computed tomography and serum bone turnover markers. Main outcomes were changes by treatment group in aBMD at LS, TH, and FA, radial and tibial trabecular BMD and cortical thickness. 70/84 patients completed assessments (40 in levetiracetam- and 30 in older AED group). Within-group analyses showed decreases in both groups in LS (-9.0 %; p < 0.001 in levetiracetam vs. -9.8 %; p < 0.001 in older AED group), FA (-1.46 %; p < 0.001 vs. -0.96 %; p < 0.001, respectively) and radial trabecular BMD (-1.46 %; p = 0.048 and -2.31 %; p = 0.013, respectively). C-terminal telopeptides of type I collagen (βCTX; bone resorption marker) decreased in both groups (-16.1 %; p = 0.021 vs. -15.2 %; p = 0.028, respectively) whereas procollagen Ι N-terminal peptide (PΙNP; bone formation marker) decreased in older AED group (-27.3 %; p = 0.008). The treatment groups did not differ in any of these measures. In conclusion, use of both levetiracetam and older AEDs was associated with bone loss over 1 year at clinically relevant fracture sites and a reduction in bone turnover. PMID:26842957

  7. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma

    PubMed Central

    Weiss, Brendan M.; Plesner, Torben; Bahlis, Nizar J.; Belch, Andrew; Lonial, Sagar; Lokhorst, Henk M.; Voorhees, Peter M.; Richardson, Paul G.; Chari, Ajai; Sasser, A. Kate; Axel, Amy; Feng, Huaibao; Uhlar, Clarissa M.; Wang, Jianping; Khan, Imran; Ahmadi, Tahamtan; Nahi, Hareth

    2016-01-01

    The efficacy and favorable safety profile of daratumumab monotherapy in multiple myeloma (MM) was previously reported. Here, we present an updated pooled analysis of 148 patients treated with daratumumab 16 mg/kg. Data were combined from part 2 of a first-in-human phase 1/2 study of patients who relapsed after or were refractory to ≥2 prior therapies and a phase 2 study of patients previously treated with ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD]) or were double refractory. Among the pooled population, patients received a median of 5 prior lines of therapy (range, 2 to 14 prior lines of therapy), and 86.5% were double refractory to a PI and an IMiD. Overall response rate was 31.1%, including 13 very good partial responses, 4 complete responses, and 3 stringent complete responses. The median duration of response was 7.6 months (95% confidence interval [CI], 5.6 to not evaluable [NE]). The median progression-free survival (PFS) and overall survival (OS) were 4.0 months (95% CI, 2.8-5.6 months) and 20.1 months (95% CI, 16.6 months to NE), respectively. When stratified by responders vs stable disease/minimal response vs progressive disease/NE, median PFS was 15.0 months (95% CI, 7.4 months to NE) vs 3.0 months (95% CI, 2.8-3.7 months) vs 0.9 months (95% CI, 0.9-1.0 months), respectively, and median OS was NE (95% CI, NE to NE) vs 18.5 months (95% CI, 15.1-22.4 months) vs 3.7 months (95% CI, 1.7-7.6 months), respectively. No new safety signals were identified. In this pooled data set, daratumumab 16 mg/kg monotherapy demonstrated rapid, deep, and durable responses, with a clinical benefit that extended to patients with stable disease or better. PMID:27216216

  8. Pegylated interferon monotherapy for hepatitis C virus infection in patients on hemodialysis: A single center study.

    PubMed

    Agarwal, S K; Bhowmik, D; Mahajan, S; Bagchi, S

    2016-01-01

    There is no published study from India on hepatitis C virus (HCV) treatment in dialysis patients. Patients on dialysis with HCV infection treated with pegylated interferon (Peg-INF) monotherapy were studied. All patients were subjected to HCV-polymerase chain reaction, viral load, genotype, and liver biopsy. Quantitative HCV-RNA was performed monthly. Patients with genotype 1 and 4 were given 12 month therapy while those with genotypes 2 and 3 were given 6 months therapy. Response was classified as per standard criteria of rapid virological response (RVR), early virological response (EVR), end of treatment response (ETR), and sustained virological response (SVR). A total of 85 patients were treated. Mean age was 35.2 ± 10.5 (range 15-67) years, and 77.6% were males. HCV genotypes were 1 in 40.9%, 2 in 12%, 3 in 36.1%, 4 in 3.6%, and others in 7.2%. Mean viral load was 10(6) copies/mL. Mean liver biopsy grade was 4 ± 1.7 and stage 0.8 ± 0.8. Mean time from diagnosis of HCV infection and the treatment start was 10.7 ± 14.3 months. One patient died of unrelated illness, one was lost to follow-up, and three could not sustain treatment due to cost. Forty-three of the 80 (54%) patients had RVR while 49 (61%) patients had EVR and ETR. There was no difference in term of RVR related to genotype. Fifty -four percentage had SVR. Mild flu-like symptoms were seen in all patients. Sixty-four (80%) patients required increase in erythropoietin doses. Twenty-eight (35%) patients developed leukopenia (three treatment-limiting) and 16 (20%) developed thrombocytopenia (one treatment-limiting). Five patients developed tuberculosis, five bacterial pneumonia, and one bacterial knee monoarthritis. None of the patients developed depression. Our study concludes that Peg-INF monotherapy resulted in 54% RVR and SVR in dialysis patients with HCV infection. Therapy was well-tolerated with minimal side effects. There was no effect of viral genotype on response to therapy. PMID:27512295

  9. Substantial Effect of Efavirenz Monotherapy on Bilirubin Levels in Healthy Volunteers

    PubMed Central

    Metzger, Ingrid F.; Quigg, Troy C.; Epstein, Noam; Aregbe, Abdulateef O.; Thong, Nancy; Callaghan, John T.; Flockhart, David A.; Nguyen, Anne T.; Stevens, Colleen K.; Gupta, Samir K.; Desta, Zeruesenay

    2014-01-01

    Background Efavirenz exhibits multiple interactions with drug-metabolizing enzymes and transporters, and for this reason efavirenz-based HIV therapy is associated with altered pharmacokinetics of coadministered drugs. Probably by the same mechanism, efavirenz-based HIV therapy affects the disposition of endogenous compounds, but this effect is difficult to directly link with efavirenz because it is used in combination with other drugs. Objectives To explore the effect of efavirenz monotherapy on biochemical laboratory values in a clinical trial of healthy volunteers. Methods Men and women (aged 18–49 years) with body mass index ≤32 who were assessed to be healthy based on medical history, physical examination, and standard laboratory screening received a single (600 mg) and multiple doses (600 mg/d for 17 days) of efavirenz orally. This trial was designed to determine the pharmacokinetics and drug interactions of efavirenz. As part of this study, analysis of serum chemistries that were measured at study entry (screening) and 1 week after completion of the multiple dose study (exit) is reported. Results Data from 60 subjects who fully completed and 13 subjects who partially completed the study are presented. Total bilirubin was substantially reduced at exit (by ~30%, with large intersubject variability) compared with screening values (P < 0.0001). The percent changes were in part explained by the intersubject differences in baseline total bilirubin because there was a significant correlation between baseline (screening) values and percent change at exit (r = 0.50; P < 0.0001). Hemoglobin and absolute neutropenia were also substantially decreased at exit compared with screening, but this may be due to intensive blood sampling rather than direct effect of efavirenz on these parameters. No significant correlation was found between percent change in hemoglobin versus percent change in bilirubin, indicating the effect of efavirenz on bilirubin is independent of its

  10. Boron-Based 4-Hydroxytamoxifen Bioisosteres for Treatment of de Novo Tamoxifen Resistant Breast Cancer

    PubMed Central

    2012-01-01

    Tamoxifen remains the first line therapy for estrogen receptor positive (ER+) breast cancer. However, polymorphisms of the gene encoding P450 2D6 could result in no protein expression or no CYP2D6 enzymatic activity and may significantly reduce the benefit of the hormone therapy. To address this issue, we designed and synthesized three 4-hydroxytamoxifen bioisosteres utilizing a boron-aryl carbon bond that can be oxidized under physiological conditions to yield 4-hydroxytamoxifen. We show that the bioisosteres inhibit the growth of two ER+ breast cancer cell lines, MCF-7 and T47D, with potencies comparable to or greater than that of 4-hydroxytamoxifen. We further demonstrate that after incubation with breast cancer cells, the majority of the bioisosteres has been converted to 4-hydroxytamoxifen. Our study suggests that boron-based 4-hydroxytamoxifen bioisosteres may be an effective therapeutic remedy for intrinsic tamoxifen resistance in breast cancer patients deficient in CYP2D6 metabolism. PMID:23864928

  11. Tamoxifen improves cytopathic effect of oncolytic adenovirus in primary glioblastoma cells mediated through autophagy

    PubMed Central

    Ulasov, Ilya V.; Shah, Nameeta; Kaverina, Natalya V.; Lee, Hwahyang; Lin, Biaoyang; Lieber, Andre; Kadagidze, Zaira G.; Yoon, Jae-Guen; Schroeder, Brett; Hothi, Parvinder; Ghosh, Dhimankrishna; Baryshnikov, Anatoly Y.; Cobbs, Charles S.

    2015-01-01

    Oncolytic gene therapy using viral vectors may provide an attractive therapeutic option for malignant gliomas. These viral vectors are designed in a way to selectively target tumor cells and spare healthy cells. To determine the translational impact, it is imperative to assess the factors that interfere with the anti-glioma effects of the oncolytic adenoviral vectors. In the current study, we evaluated the efficacy of survivin-driven oncolytic adenoviruses pseudotyping with adenoviral fiber knob belonging to the adenoviral serotype 3, 11 and 35 in their ability to kill glioblastoma (GBM) cells selectively without affecting normal cells. Our results indicate that all recombinant vectors used in the study can effectively target GBM in vitro with high specificity, especially the 3 knob-modified vector. Using intracranial U87 and U251 GBM xenograft models we have also demonstrated that treatment with Conditionally Replicative Adenovirus (CRAd-S-5/3) vectors can effectively regress tumor. However, in several patient-derived GBM cell lines, cells exhibited resistance to the CRAd infection as evident from the diminishing effects of autophagy. To improve therapeutic response, tumor cells were pretreated with tamoxifen. Our preliminary data suggest that tamoxifen sensitizes glioblastoma cells towards oncolytic treatment with CRAd-S-5/3, which may prove useful for GBM in future experimental therapy. PMID:25738357

  12. Long chain lipid based tamoxifen NLC. Part I: preformulation studies, formulation development and physicochemical characterization.

    PubMed

    Shete, Harshad; Patravale, Vandana

    2013-09-15

    Tamoxifen citrate (Tmx) was formulated in nanostructured lipid carrier system (NLC) using long chain solid lipids (LCSL) and oils (LCO) with the aim to target lymphatic system to improve its bioavailability in plasma and lymphnode (initial sites for metastasis) and reduce its drug associated toxicity. Tamoxifen loaded NLC (Tmx-NLC) was formulated using solvent diffusion technique. Preformulation studies comprised evaluation of drug-excipients compatibility. Solubility of Tmx was screened in LCSL and LCO, surfactants and co-surfactants to identify NLC components. Surfactant co-surfactant combinations were studied for their ability to stabilize the system. Tmx-NLC was physicochemically characterized by TEM, DSC, XRD, and FTIR studies. Drug-excipients chemical compatibility study facilitated anticipation of excipients induced oxidative degradation of Tmx. Suitable storage condition below 30°C could stabilize Tmx. Tmx-NLC with >90% entrapment efficiency and 215.60 ± 7.98 nm particle size were prepared and freeze dried. Freeze dried Tmx-NLC could withstand various gastrointestinal tract (GI) media (pH 1.2, pH 3.5, pH 4.5, pH 6.8, pH 7.4). Dissolution profile of Tmx-NLC in various media showed sustained release pattern irrespective of pH of medium. No significant change in characteristics of Tmx-NLC was observed after 3 months of accelerated stability studies. PMID:23535345

  13. Effects of CreERT2, 4-OH Tamoxifen, and Gender on CFU-F Assays

    PubMed Central

    McHaffie, Sophie L.; Hastie, Nicholas D.; Chau, You-Ying

    2016-01-01

    Gene function in stem cell maintenance is often tested by inducing deletion via the Cre-loxP system. However, controls for Cre and other variables are frequently not included. Here we show that when cultured in the presence of 4-OH tamoxifen, bone and marrow cells containing the CreERT2 construct have a reduced colony forming ability. Inactive CreERT2 recombinase, however, has the opposite effect. Young female marrow cells containing the inactive CreERT2 construct grew more colonies than cells lacking the const