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Sample records for adjuvant tamoxifen monotherapy

  1. Clinical importance of androgen receptor in breast cancer patients treated with adjuvant tamoxifen monotherapy.

    PubMed

    Honma, Naoko; Horii, Rie; Iwase, Takuji; Saji, Shigehira; Younes, Mamoun; Ito, Yoshinori; Akiyama, Futoshi

    2012-02-01

    BACKGROUND: Despite many studies, the clinicopathological importance of the androgen receptor (AR) in breast cancer is not well established, and its significance as an independent predictor of clinical outcome is controversial. A large and systematic study is needed to address these issues. The aim of the present study was to elucidate whether AR has independent clinical value, examining its importance in a large and well-predefined patient group with a long follow-up period and complete clinicopathological data. METHODS: Archival materials of 403 invasive breast cancers from women treated with adjuvant tamoxifen monotherapy (median follow-up period 11.0 years) were subjected to immunohistochemical study using anti-AR monoclonal antibody. AR expression was compared with established clinicopathological factors, estrogen receptor (ER)-β expression, and clinical outcome. RESULTS: AR positivity was correlated with ER-α positivity, progesterone receptor positivity, ER-β positivity, and a lower nuclear grade. Patients with AR-positive carcinomas exhibited a significantly better clinical outcome than those with AR-negative carcinomas (P = 0.0165 for disease-free survival, P = 0.0344 for overall survival). Multivariate analysis did not yield significant differences in clinical outcome according to the AR status, whereas the ER-β status showed significant differences in multivariate analysis. CONCLUSIONS: Although, and in agreement with previous reports, AR positivity correlated with some established favorable prognostic factors and with ER-β positivity, AR was not an independent predictor of clinical outcome. Controversy regarding the value of AR as an independent predictor of clinical outcome may at least partly reflect the relatively limited power of AR in breast cancer. PMID:22302643

  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. 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

  4. Outcome in patients with idiopathic retroperitoneal fibrosis treated with corticosteroid or tamoxifen monotherapy

    PubMed Central

    van der Bilt, Floor E.; Hendriksz, Tadek R.; van der Meijden, Wilbert A.G.; Brilman, Lisette G.; van Bommel, Eric F.H.

    2016-01-01

    Background Although corticosteroids (CS) are used primarily in idiopathic retroperitoneal fibrosis (iRPF), tamoxifen (TMX) may be a suitable alternative. We compared outcome with CS or TMX monotherapy for first presentation in a large group of patients with iRPF disease. Methods Of all patients with iRPF disease who were seen at our tertiary care referral centre from February 1999 to December 2011, 118 patients were eligible for this retrospective study. Treatment success was defined as the composite of (i) amelioration of symptoms, (ii) computed tomography (CT)-documented mass regression and, if applicable, (iii) definitive removal of ureteral stent or nephrostomy tube. Recurrence was defined as recurrence of signs and symptoms and/or CT-documented mass increase after initial treatment success with primary treatment. Results Presenting signs and symptoms did not differ between patients treated with CS (n = 50) or TMX (n = 68). Time to amelioration of symptoms after treatment initiation was shorter in CS-treated patients [CS, 2.0 (0.8–3.8) weeks versus TMX, 4.0 (2.0–6.0) weeks; P < 0.01]. Short-term percentual decrease in acute-phase reactant levels (P < 0.001 for both erythrocyte sedimentation rate and C-reactive protein) and serum creatinine level (P < 0.01) following treatment initiation was greater in CS-treated patients compared with that in TMX-treated patients. Mass regression at first follow-up CT scan was observed more frequently in CS-treated patients (CS, 84.0% versus TMX, 68.3%; P = 0.05) with no difference in time interval from treatment initiation to first follow-up CT between groups [CS, 5 (2–7) months versus TMX, 4 (4–5) months; P = 0.34]. Definite treatment success was non-significantly higher in CS-treated patients (CS, 72.7% versus TMX, 58.3%; P = 0.15). In patients with initial treatment success with primary treatment, recurrence rate was lower in TMX-treated patients (CS, 62.5% versus TMX, 21.4%; P < 0.01). Conclusions CS are superior

  5. 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

  6. 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

  7. 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

  8. Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen.

    PubMed

    Markopoulos, Christos; Kykalos, Stylianos; Mantas, Dimitrios

    2014-08-10

    Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome. PMID:25114852

  9. Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

    PubMed Central

    Markopoulos, Christos; Kykalos, Stylianos; Mantas, Dimitrios

    2014-01-01

    Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome. PMID:25114852

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

    PubMed

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

    2015-12-01

    In early adjuvant breast cancer trial reports, aromatase inhibitors more effectively reduced breast recurrence with lower risk of thromboembolic events and endometrial cancer than tamoxifen, while aromatase inhibitors had higher fracture and cardiovascular disease risk. We used data from updated patient-level meta-analyses of adjuvant trials in analyses to summarize the benefits and risks of these agents in various clinical circumstances. Baseline incidence rates for health outcomes by age and race/ethnicity, absent aromatase inhibitor, or tamoxifen use were estimated from the Women's Health Initiative. Aromatase inhibitor and tamoxifen effects on distant recurrence were obtained from a meta-analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) and Breast International Group (Big-1-98) clinical trials. Impact on other health outcomes were obtained from meta-analyses of randomized trials comparing aromatase inhibitor to tamoxifen use and from placebo-controlled chemoprevention trials. All health outcomes were given equal weight when modeling net benefit/risk for aromatase inhibitor compared to tamoxifen use by breast cancer recurrence risk, age (decade), race/ethnicity, hysterectomy (yes/no), and by prior myocardial infarction. Over a 10-year period, the benefit/risk index was more favorable for aromatase inhibitor than for tamoxifen as adjuvant breast cancer therapy in almost all circumstances regardless of patient age, race/ethnicity, breast cancer recurrence risk, or presence or absence of a uterus. Only in older women with prior myocardial infarction and low recurrence risk was an advantage for tamoxifen seen. Using a benefit/risk index for endocrine adjuvant breast cancer therapy in postmenopausal women, benefit was higher for aromatase inhibitor use in almost all circumstances. PMID:26602222

  11. 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

  12. Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment.

    PubMed

    Ramón y Cajal, T; Altés, A; Paré, L; del Rio, E; Alonso, C; Barnadas, A; Baiget, M

    2010-01-01

    The aim of this study is to evaluate the impact of CYP2D6 genotyping in predicting disease-free survival and toxicity in breast cancer patients treated with adjuvant tamoxifen. DNA from 91 patients was genotyped using the AmpliChip CYP450 GeneChip, Roche that facilitates the classification of individuals by testing 27 alleles. When patients were grouped into group 1 (*4/*4, *4/*41, *1/*5 and *2/*5) and group 2 (the remaining genotypes), a significant difference in disease-free survival (DFS) was observed between groups (P = 0.016). The mean DFS in group 1 was 95 months in contrast with 119 months in group 2. No significant relationship was found between the CYP2D6 genotype classification and severe, mild or no toxicity (P = 0.2). Nevertheless, severe, and mild toxicity was more frequent among poor metabolizer patients than in patients with a normal metabolizer pattern (18.8 and 43.8% vs. 10.7 and 36%, respectively). In breast cancer, patients treated with adjuvant tamoxifen, non-functional and severely impaired CYP2D6 variants are associated with a worse DFS and with a higher frequency of severe and mild toxicities. Larger studies of the CYP2D6 genotype-clinical outcomes association are needed to complement initial results. PMID:19189210

  13. Tamoxifen

    MedlinePlus

    ... the disease due to their age, personal medical history, and family medical history.Tamoxifen is in a class of medications known ... the fetus.tell your doctor if you are breast-feeding. You should not breastfeed during your treatment with ...

  14. Phosphorylated p-70S6K predicts tamoxifen resistance in postmenopausal breast cancer patients randomized between adjuvant tamoxifen versus no systemic treatment

    PubMed Central

    2014-01-01

    Introduction Activation of the phosphatidylinositol-3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways results in anti-estrogen resistance in vitro, but a biomarker with clinical validity to predict intrinsic resistance has not been identified. In metastatic breast cancer patients with previous exposure to endocrine therapy, the addition of a mammalian target of rapamycine (mTOR) inhibitor has been shown to be beneficial. Whether or not patients on adjuvant endocrine treatment might benefit from these drugs is currently unclear. A biomarker that predicts intrinsic resistance could potentially be used as companion diagnostic in this setting. We tested the clinical validity of different downstream-activated proteins in the PI3K and/or MAPK pathways to predict intrinsic tamoxifen resistance in postmenopausal primary breast cancer patients. Methods We recollected primary tumor tissue from patients who participated in a randomized trial of adjuvant tamoxifen (1–3 years) versus observation. After constructing a tissue micro-array, cores from 563 estrogen receptor α positive were immunostained for p-AKT(Thr308), p-AKT(Ser473), p-mTOR, p-p706SK and p-ERK1/2. Cox proportional hazard models for recurrence free interval were used to assess hazard ratios and interactions between these markers and tamoxifen treatment efficacy. Results Interactions were identified between tamoxifen and p-AKT(Thr308), p-mTOR, p-p70S6K and p-ERK1/2. Applying a conservative level of significance, p-p70S6K remained significantly associated with tamoxifen resistance. Patients with p-p70S6K negative tumors derived significant benefit from tamoxifen (HR 0.24, P < 0.0001), while patients whose tumor did express p-p70S6K did not (HR = 1.02, P =0.95), P for interaction 0.004. In systemically untreated breast cancer patients, p-p70S6K was associated with a decreased risk for recurrence. Conclusions Patients whose tumor expresses p-p70S6K, as a marker of downstream PI3K and

  15. AB093. The efficacy of medical treatment of Peyronie’s disease: Potaba monotherapy vs. combination therapy with Tamoxifen, L-carnitine, and PDE5 inhibitor

    PubMed Central

    Park, Jong Jin; Kim, Jong Wook; Moon, Du Geon

    2016-01-01

    Objective This study was designed to evaluate the efficacy of combination therapy of Tamoxifen, L-carnitine and daily PDE5 inhibitors and to compare with Potassium para-aminobenzoate (Potaba) monotherapy in the medical treatment of Peyronie’s disease. Methods From January 2011 to December 2014, a total of 104 patients with Peyronie’s disease enrolled in this study. Sixty-eight patients were treated with Tamoxifen 20 mg and Acetyl L-carnitine 330 mg twice a daily in addition to daily PDE5 inhibitors (Tadalafil 5 mg once daily) combination therapy (Group 1), while thirty-four patients were treated with Potassium para-aminobenzoate 12 g daily (Group 2), Pain on erection, impossibility of intercourse, plaque size, penile curvature and IIEF-5 were assessed. Plaque volume was assessed by penile ultrasonography. Results Both groups showed resolution of pain and intercourse satisfaction after treatment. The pre-treatment plaque sizes of both groups were 17.1±7.2, 17.0±5.0 mm, respectively. After treatment, those parameters significantly reduced to 13.2±5.6, 16.2±5.3 mm. In group 1, combination therapy significantly improved the angle of penile curvature, plaque size, and IIEF (P<0.05). In group 2, the size of the plaque, penile curvature and IIEF were improved after Potassium para-aminobenzoate monotherapy. However, no significant differences were observed. Conclusions Statistically significant improvement in intercourse satisfaction, plaque size, degree of curvature and IIEF-5 was observed in combination therapy. Combination therapy may be the more effective than Potassium para-aminobenzoate monotherapy in medical treatment of Pyeronie’s disease.

  16. Meta-analysis of trials comparing anastrozole and tamoxifen for adjuvant treatment of postmenopausal women with early breast cancer

    PubMed Central

    Aydiner, Adnan; Tas, Faruk

    2008-01-01

    Objective It was aimed to review the literature and make a meta-analysis of the trials on both upfront, switching, and sequencing anastrozole in the adjuvant treatment of early breast cancer. Methods The PubMed, ClinicalTrials.gov and Cochrane databases were systematically reviewed for randomized-controlled trials comparing anastrozole with tamoxifen in the adjuvant treatment of early breast cancer. Results The combined hazard rate of 4 trials for event-free survival (EFS) was 0.77 (95%CI: 0.70–0.85) (P < 0.0001) for patients treated with anastrozole compared with tamoxifen. In the second analysis in which only ITA, ABCSG 8, and ARNO 95 trials were included and ATAC (upfront trial) was excluded, combined hazard rate for EFS was 0.64 (95%CI: 0.52–0.79) (P < 0.0001). In the third analysis including hazard rate for recurrence-free survival (excluding non-disease related deaths) of estrogen receptor-positive patients for ATAC trial and hazard rate for EFS of all patients for the rest of the trials, combined hazard rate was 0.73 (95%CI: 0.65–0.81) (P < 0.0001). Conclusion Anastrozole appears to have superior efficacy than tamoxifen in the adjuvant hormonal treatment of early breast cancer. Until further clinical evidence comes up, aromatase inhibitors should be the initial hormonal therapy in postmenopausal early breast cancer patients and switching should only be considered for patients who are currently receiving tamoxifen. PMID:18664277

  17. 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

  18. CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations.

    PubMed

    Province, M A; Goetz, M P; Brauch, H; Flockhart, D A; Hebert, J M; Whaley, R; Suman, V J; Schroth, W; Winter, S; Zembutsu, H; Mushiroda, T; Newman, W G; Lee, M-T M; Ambrosone, C B; Beckmann, M W; Choi, J-Y; Dieudonné, A-S; Fasching, P A; Ferraldeschi, R; Gong, L; Haschke-Becher, E; Howell, A; Jordan, L B; Hamann, U; Kiyotani, K; Krippl, P; Lambrechts, D; Latif, A; Langsenlehner, U; Lorizio, W; Neven, P; Nguyen, A T; Park, B-W; Purdie, C A; Quinlan, P; Renner, W; Schmidt, M; Schwab, M; Shin, J-G; Stingl, J C; Wegman, P; Wingren, S; Wu, A H B; Ziv, E; Zirpoli, G; Thompson, A M; Jordan, V C; Nakamura, Y; Altman, R B; Ames, M M; Weinshilboum, R M; Eichelbaum, M; Ingle, J N; Klein, T E

    2014-02-01

    The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy. PMID:24060820

  19. 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.

  20. Pak1, adjuvant tamoxifen therapy, and breast cancer recurrence risk in a Danish population-based study.

    PubMed

    Ahern, Thomas P; Cronin-Fenton, Deirdre P; Lash, Timothy L; Sørensen, Henrik Toft; Ording, Anne Gulbech; Hamilton-Dutoit, Stephen J; Hellberg, Ylva

    2016-06-01

    Background Adjuvant tamoxifen therapy approximately halves the risk of estrogen receptor-positive (ER+) breast cancer recurrence, but many women do not respond to therapy. Observational studies nested in clinical trial populations suggest that overexpression or nuclear localization of p21-activated kinase 1 (Pak1) in primary tumors predicts tamoxifen failure. Material and methods We measured the association between Pak1 expression and breast cancer recurrence in a Danish population-based case-control study. Pak1 cytoplasmic expression level and nuclear positivity were determined by immunohistochemical staining of primary breast tumors from recurrence cases and matched controls from two breast cancer populations; women diagnosed with ER-positive tumors who received at least one year of tamoxifen therapy (ER+/TAM+), and women diagnosed with ER-negative tumors who survived for at least one year (ER-/TAM-). Pak1 staining was assessed by a single, blinded pathologist, and associations were estimated with conditional logistic regression models. Results We included 541 recurrence cases and 1:1 matched controls from the ER+/TAM + group and 300 recurrence cases and 1:1 matched controls from the ER-/TAM - group. Pak1 cytoplasmic intensity was not associated with breast cancer recurrence in either group (ER+/TAM + ORadj for strong vs. no cytoplasmic staining = 0.91, 95% CI 0.57, 1.5; ER-/TAM - ORadj for strong vs. no cytoplasmic staining = 0.74, 95% CI 0.39, 1.4). Associations between Pak1 nuclear positivity and breast cancer recurrence were similarly near null in both groups. Conclusion Pak1 positivity in primary breast tumors was neither predictive nor prognostic in this prospective, population-based study. PMID:27056567

  1. 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

  2. Significant Effect of Polymorphisms in CYP2D6 and ABCC2 on Clinical Outcomes of Adjuvant Tamoxifen Therapy for Breast Cancer Patients

    PubMed Central

    Kiyotani, Kazuma; Mushiroda, Taisei; Imamura, Chiyo K.; Hosono, Naoya; Tsunoda, Tatsuhiko; Kubo, Michiaki; Tanigawara, Yusuke; Flockhart, David A.; Desta, Zeruesenay; Skaar, Todd C.; Aki, Fuminori; Hirata, Koichi; Takatsuka, Yuichi; Okazaki, Minoru; Ohsumi, Shozo; Yamakawa, Takashi; Sasa, Mitsunori; Nakamura, Yusuke; Zembutsu, Hitoshi

    2010-01-01

    Purpose The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism, and elimination of its active forms. We investigated relationships of polymorphisms in transporter genes and CYP2D6 to clinical outcome of patients receiving tamoxifen. Patients and Methods We studied 282 patients with hormone receptor–positive, invasive breast cancer receiving tamoxifen monotherapy, including 67 patients who have been previously reported. We investigated the effects of allelic variants of CYP2D6 and haplotype-tagging single nucleotide polymorphisms (tag-SNPs) of ABCB1, ABCC2, and ABCG2 on recurrence-free survival using the Kaplan-Meier method and Cox regression analysis. Plasma concentrations of tamoxifen metabolites were measured in 98 patients receiving tamoxifen 20 mg/d. Results CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = .000036; hazard ratio [HR] = 9.52; 95% CI, 2.79 to 32.45 in patients with two variant alleles v patients without variant alleles). Among 51 tag-SNPs in transporter genes, a significant association was found at rs3740065 in ABCC2 (P = .00017; HR = 10.64; 95% CI, 1.44 to 78.88 in patients with AA v GG genotypes). The number of risk alleles of CYP2D6 and ABCC2 showed cumulative effects on recurrence-free survival (P = .000000055). Patients carrying four risk alleles had 45.25-fold higher risk compared with patients with ≤ one risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = .0000043 and .00052), whereas no significant difference was found among ABCC2 genotype groups. Conclusion Our results suggest that polymorphisms in CYP2D6 and ABCC2 are important predictors for the prognosis of patients with breast cancer treated with tamoxifen. PMID:20124171

  3. Bone mineral density and circulating biomarkers in the BIG 1-98 trial comparing adjuvant letrozole, tamoxifen and their sequences

    PubMed Central

    DeCensi, Andrea; Sun, Zhuoxin; Guerrieri-Gonzaga, Aliana; Thürlimann, Beat; McIntosh, Christina; Tondini, Carlo; Monnier, Alain; Campone, Mario; Debled, Marc; Schönenberger, Astrid; Zaman, Khalil; Johansson, Harriet; Price, Karen N.; Gelber, Richard D.; Goldhirsch, Aron; Coates, Alan S.; Aebi, Stefan

    2014-01-01

    Purpose To determine the effects of the BIG 1-98 treatments on bone mineral density. BIG 1-98 compared 5-year adjuvant hormone therapy in postmenopausal women allocated to four groups: tamoxifen (T); letrozole (L); 2-years T, 3-years L (TL); 2-years L, 3-years T (LT). Methods Bone mineral density T-score was measured prospectively annually by dual energy X-ray absorption in 424 patients enrolled in a sub-study after three (n=150), four (n=200), and five years (n=74) from randomization, and one year after treatment cessation. Prevalence of osteoporosis and the association of C-telopeptide, osteocalcin and bone alkaline phosphatase with T-scores were assessed. Results At 3 years, T had the highest and TL the lowest T-score. All arms except for LT showed a decline up to 5 years, with TL exhibiting the greatest. At 5 years, there were significant differences on lumbar T-score only between T and TL, whereas for femur T-score differences were significant for T vs. L or TL, and L vs. LT. The 5-year prevalence of spine and femur osteoporosis was highest on TL (14.5%, 7.1%) then L (4.3%, 5.1%), LT (4.2%, 1.4%) and T (4%, 0). C-telopeptide and osteocalcin were significantly associated with T-scores. Conclusions While adjuvant L increases bone mineral density loss compared with T, the sequence LT has an acceptable bone safety profile. C-telopeptide and osteocalcin are useful markers of bone density that may be used to monitor bone health during treatment. The sequence LT may be a valid treatment option in patients with low and intermediate risk of recurrence. Trial registration clinicaltrials.gov NCT00369850 PMID:24487691

  4. Contribution of ABCB1 and CYP2D6 genotypes to the outcome of tamoxifen adjuvant treatment in premenopausal women with breast cancer.

    PubMed

    Argalácsová, S; Slanař, O; Vítek, P; Tesařová, P; Bakhouche, H; DraŽďáková, M; Bartošová, O; Zima, T; PertuŽelka, L

    2015-01-01

    Recent pre-clinical evidence suggests that the active metabolite of tamoxifen, endoxifen, is a substrate for efflux pump P-glycoprotein. The aim of our study was to evaluate, if the polymoprhisms within ABCB1 gene alter tamoxifen adjuvant treatment efficacy in premenopausal women. Totally 71 premenopausal women with estrogen receptor positive breast cancer indicated for tamoxifen adjuvant treatment were followed retrospectively for median period of 56 months. The gentic polymorphisms of CYP2D6 and ABCB1 were analyzed and potential covariates as tumor grading, staging, age at the diagnosis, comedication, quantitative positivity of ER or PR were also evaluated. Cox proportional-hazards regression model indicated that patients carrying at least one variant allele in ABCB1 rs1045642 had significantly longer time to event survival compared to wild type subjects. Non-significant trend was noted for better treatment outcome of patients carrying at least one variant allele in the SNP rs2032582, while for the CYP2D6 polymorphism poor metabolizer phenotype resulted in worse outcome in comparison to extensive metabolizers subjects with HR of 4.04 (95 % CI 0.31-52.19). Similarly, patients using CYP2D6 inhibitors had non-significantly shorter time-to-event as compared to never users resulting in hazard ratio of 2.06 (95 % CI 0.40-10.63). ABCB1 polymorphisms may affect outcome of tamoxifen adjuvant treatment in premenopausal breast cancer patiens. This factor should be taken into account in addition to the CYP2D6 polymorphism or phenotypic inhibition of CYP2D6 activity. PMID:26681084

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

    PubMed Central

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

    2008-01-01

    Background Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30–40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings. Results We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29–3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response. Conclusion We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen. PMID:18498629

  6. 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

  7. 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.

  8. 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. PMID:27117241

  9. 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

  10. Adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression: patient-reported outcomes in the TEXT and SOFT randomised trials

    PubMed Central

    Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Colleoni, Marco; Burstein, Harold J.; Tondini, Carlo; Pinotti, Graziella; Spazzapan, Simon; Ruhstaller, Thomas; Puglisi, Fabio; Pavesi, Lorenzo; Parmar, Vani; Regan, Meredith M.; Pagani, Olivia; Fleming, Gini F.; Francis, Prudence A.; Price, Karen N.; Coates, Alan S.; Gelber, Richard D.; Goldhirsch, Aron; Walley, Barbara A.

    2015-01-01

    Background Efficacy analysis of the combined IBCSG TEXT and SOFT trials showed a significant disease-free survival benefit for exemestane plus ovarian function suppression (OFS) compared with tamoxifen +OFS. We present patient-reported outcomes from these trials. Methods Between 7 November 2003 and 7 April 2011, 4717 premenopausal patients with hormone-receptor positive breast cancer were enrolled in TEXT or SOFT to receive unblinded adjuvant treatment with 5 years of exemestane+OFS or tamoxifen+OFS. Chemotherapy use was optional. Randomization was performed via IBCSG’s internet-based system with the use of permuted blocks and was stratified by chemotherapy use and lymph nodes status. Patients completed a quality of life (QoL) form including several global and symptom-specific indicators at baseline, every 6 months for 24 months, then annually during years 3 to 6. Differences in change of QoL from baseline between the two treatments were tested at short-, mid-, and long-term using mixed-models for repeated measures, for each trial with and without chemotherapy and overall. The analysis was intention-to-treat using treatment as randomly assigned. At the time of analysis, the median follow-up was 5·7 years (IQR, 3·7 to 6·9 years), with treatment and follow-up of patients ongoing. Findings Patients reported considerable worsening from baseline in key endocrine symptoms. Those on tamoxifen+OFS were more affected by hot flushes and sweats over five years than those on exemestane+OFS, although these symptoms improved. Patients on exemestane+OFS reported more vaginal dryness, greater loss of sexual interest, and difficulties becoming aroused. These differences persisted over time. An increase in bone/joint pain was more pronounced, particularly in the short-term, in patients on exemestane+OFS. Changes of global QoL indicators from baseline were small and similar between treatments over the whole treatment period. Interpretation Overall, from a QoL perspective, there

  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. 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

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

    PubMed Central

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

    2014-01-01

    Background One of the first chemoprevention trials conducted in the western hemisphere, the National Surgical Adjuvant Breast and Bowel Project’s (NSABP) Breast Cancer Prevention Trial (BCPT), demonstrated the need to evaluate all aspects of recruitment in real time and to implement strategies to enroll racial and ethnic minority women. Purpose The purpose of this report is to review various patient recruitment efforts the NSABP developed to enhance the participation of racial and ethnic minority women in the Study of Tamoxifen and Raloxifene (STAR) trial and to describe the role that the recruitment process played in the implementation and understanding of breast cancer risk assessment in minority communities. Methods The NSABP STAR trial was a randomized, double-blinded study comparing the use of tamoxifen 20 mg/day to raloxifene 60 mg/day, for a 5-year period, to reduce the risk of developing invasive breast cancer. Eligible postmenopausal women were required to have a 5-year predicted breast cancer risk of 1.66% based on the modified Gail Model. For the current report, eligibility and enrollment data were tabulated by race/ethnicity for women who submitted STAR risk assessment forms (RAFs). Results A total of 184,460 RAFs were received, 145,550 (78.9%) from white women and 38,910 (21.1%) from minority women. Of the latter group, 21,444 (11.6%) were from African Americans/blacks, 7913 (4.5%) from Hispanics/Latinas, and 9553 (5.2%) from other racial or ethnic groups. The percentages of risk-eligible women among African Americans, Hispanics/Latinas, others, and whites were 14.2%, 23.3%, 13.7%, and 57.4%, respectively. Programs targeting minority enrollment submitted large numbers of RAFs, but the eligibility rates of the women referred from those groups tended to be lower than the rates among women referred outside of those programs. The average number of completed risk assessments increased among minority women over the course of the recruitment period compared

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

    PubMed

    Mokbel, Ramia; Karat, Isabella; Mokbel, Kefah

    2006-01-01

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

  15. PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients

    PubMed Central

    2014-01-01

    Introduction Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) α-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERα-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERα-positive breast cancer is contradictive. We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen. In addition, we tested the association between these drivers and downstream activated proteins. Methods Primary tumors from 563 ERα-positive postmenopausal patients, randomized between adjuvant tamoxifen (1 to 3 years) versus observation were recollected. PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry. Immunohistochemistry was performed for human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and insulin-like growth factor 1 receptor (IGF-1R). We tested the association between these molecular alterations and downstream activated proteins (like phospho-protein kinase B (p-AKT), phospho-mammalian target of rapamycin (p-mTOR), p-ERK1/2, and p-p70S6K). Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers, by using Cox proportional hazard models, including a test for interaction. Results PIK3CA mutations (both exon 9 and exon 20) were associated with low tumor grade. An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors. PIK3CA exon 20 mutations were not associated with downstream-activated proteins. No significant interaction between PIK3CA mutations or any

  16. Postmenopausal tamoxifen treatment and endometrial pathology.

    PubMed

    Cohen, I; Altaras, M M; Shapira, J; Tepper, R; Beyth, Y

    1994-12-01

    Tamoxifen is widely used as adjuvant therapy for postmenopausal breast cancer patients with positive estrogen receptors. Data on a possible association of endometrial pathologies with tamoxifen treatment have been accumulating. In this review, we examine the current literature and include our own experience with this occurrence. We recommend close supervision of these patients. PMID:7885659

  17. 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

    Regan, Meredith M; Price, Karen N; Giobbie-Hurder, Anita; Thürlimann, Beat; Gelber, Richard D

    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

  18. 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

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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

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

    PubMed Central

    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

  9. 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

  10. [New options in adjuvant endocrine therapy in breast cancer].

    PubMed

    Saltel-Fulero, Aurélien; Donnadieu, Anne; Leman-Detours, Solenne; Cottu, Paul

    2016-01-01

    Endocrine therapy is a compulsory step in the adjuvant management of early breast cancer expressing the estrogen receptor, by reducing as much as possible serum and tissue levels of estrogens. Tamoxifen is the standard therapy for non-menopausal women. Ovarian function suppression, in addition to exemestane or tamoxifen, could be an alternative option for young women at high risk of recurrence and non menopausal after adjuvant or neo-adjuvant chemotherapy. Recent studies show a trend for improvement of overall survival and disease-free-survival with aromatase inhibitors among postmenopausal women. However, safety of aromatase inhibitors is controversial and adverse events may lead to switch for tamoxifen with no loss of efficacy. Extension therapy by tamoxifen or aromatase inhibitor after five years of tamoxifen and for a total duration of ten years significantly improves overall survival. There is to date no data supporting the extension therapy after five years of aromatase inhibitor. PMID:26675809

  11. Aromatase inhibitors alone or sequentially combined with tamoxifen in postmenopausal early breast cancer compared with tamoxifen or placebo - Meta-analyses on efficacy and adverse events based on randomized clinical trials.

    PubMed

    Rydén, Lisa; Heibert Arnlind, Marianne; Vitols, Sigurd; Höistad, Malin; Ahlgren, Johan

    2016-04-01

    Tamoxifen (TAM) and aromatase inhibitors (AI) are adjuvant therapy options for postmenopausal women with estrogen receptor positive (ER+) breast cancer. This systematic review of seven randomized controlled studies comparing TAM and AI, and one study comparing extended therapy with an AI with placebo after about 5 years of tamoxifen, aims to assess long-term clinical efficacy and adverse events. The literature review was performed according to the principles of the Cochrane Collaboration. The search included common databases up to 2013-01-14. Studies of high or moderate quality were used for grading of evidence. Revman™ software was utilized for meta-analyses of published data. Disease free survival (DFS) and overall survival (OS) were improved with AI monotherapy compared to TAM with high and moderate quality of evidence respectively. Sequenced therapy with AI → TAM (or vice versa) improved DFS compared with TAM with moderate quality of evidence, but did not improve OS (low quality of evidence). However, if only studies on sequenced AI therapy with randomization before endocrine therapy were considered, no improvement of DFS could be found. Fractures are more frequently associated with AI whereas the risk of endometrial cancer and venous thromboembolism are higher with TAM. For cardiovascular events no difference was found between AI (mono- or sequenced therapy) and TAM, whereas sequenced therapy compared with AI had lower risk of cardiovascular events (moderate level of evidence). AIs are superior to TAM as adjuvant hormonal therapy for postmenopausal ER-positive breast cancer. TAM can be considered for individual patients due to the different toxicity profile compared with AI. Cardiovascular events related to AI treatment deserve further attention. PMID:27017249

  12. Combinatorial Therapy with Tamoxifen And Trifluoperazine Effectively Inhibits Malignant Peripheral Nerve Sheath Tumor Growth by Targeting Complementary Signaling Cascades

    PubMed Central

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

    2014-01-01

    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 NF1-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. Additionally, 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. PMID:25289889

  13. 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

  14. Improved adjuvant endocrine therapy for premenopausal women with endocrine responsive disease

    PubMed Central

    Goldhirsch, Aron; Colleoni, Marco; Regan, Meredith

    2015-01-01

    Results from two randomised global trials (SOFT & TEXT) designed to newly define the most effective components of adjuvant endocrine therapy for premenopausal women with endocrine responsive disease, showed that for some, those with high risk of relapse, the use of the aromatase inhibitor exemestane together with ovarian function suppression with GnRH analogue (triptorelin) yielded the most favourable treatment outcome compared with tamoxifen. For women with low risk of relapse, treatment with tamoxifen was similar to ovarian function suppression together with either exemestane or tamoxifen. For women with intermediate risk of relapse, ovarian function suppression added to tamoxifen was not inferior to exemestane, while it resulted in superior outcomes compared to tamoxifen alone. Now, these trials provide critical information for the adjuvant treatment of premenopausal women with endocrine responsive breast cancer and are important for the development of future trials for further improvement of adjuvant endocrine therapies for the younger population. PMID:26082801

  15. USP9X downregulation renders breast cancer cells resistant to tamoxifen.

    PubMed

    Oosterkamp, Hendrika M; Hijmans, E Marielle; Brummelkamp, Thijn R; Canisius, Sander; Wessels, Lodewyk F A; Zwart, Wilbert; Bernards, René

    2014-07-15

    Tamoxifen is one of the most widely used endocrine agents for the treatment of estrogen receptor α (ERα)-positive breast cancer. Although effective in most patients, resistance to tamoxifen is a clinically significant problem and the mechanisms responsible remain elusive. To address this problem, we performed a large scale loss-of-function genetic screen in ZR-75-1 luminal breast cancer cells to identify candidate resistance genes. In this manner, we found that loss of function in the deubiquitinase USP9X prevented proliferation arrest by tamoxifen, but not by the ER downregulator fulvestrant. RNAi-mediated attenuation of USP9X was sufficient to stabilize ERα on chromatin in the presence of tamoxifen, causing a global tamoxifen-driven activation of ERα-responsive genes. Using a gene signature defined by their differential expression after USP9X attenuation in the presence of tamoxifen, we were able to define patients with ERα-positive breast cancer experiencing a poor outcome after adjuvant treatment with tamoxifen. The signature was specific in its lack of correlation with survival in patients with breast cancer who did not receive endocrine therapy. Overall, our findings identify a gene signature as a candidate biomarker of response to tamoxifen in breast cancer. PMID:25028367

  16. Monotherapy versus combination therapy.

    PubMed

    Patel, Shilpa M; Saravolatz, Louis D

    2006-11-01

    The science of antibiotic therapy for infectious diseases continues to evolve. In many instances where empiric coverage is necessary, treatment with more than one agent is considered prudent. If an etiology is identified, antibiotics are modified based on culture and susceptibility data. Even when the organism is known, more than one antibiotic may be needed. Decisions about antibiotics should be made after assessments of pertinent clinical information, laboratory and microbiology information, ease of administration, patient compliance, potential adverse effects, cost, and available evidence supporting various treatment options. Clinicians also need to consider synergy and local resistance patterns in selecting therapeutic options. In this article, the authors outline monotherapy and combination therapy options for several common infectious diseases. PMID:17116443

  17. 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

  18. Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs.

    PubMed

    Yang, Geniey; Nowsheen, Somaira; Aziz, Khaled; Georgakilas, Alexandros G

    2013-09-01

    Breast cancer is a heterogeneous disease affecting thousands of people every year. Multiple factors are responsible in causing breast cancer while a number of treatment options are also available for the disease. Tamoxifen is the most widely used anti-estrogen for the treatment of hormone-dependent breast cancer. The specific drug is used as a hormonal therapy for patients who exhibit estrogen receptor positive breast cancer. The pharmacological activity of Tamoxifen is dependent on its conversion to its active metabolite, endoxifen, by CYP2D6. Tamoxifen reduces the risk of recurrence and death from breast cancer when given as adjuvant therapy and provides effective palliation for patients with metastatic breast cancer. In this review we focus on the role of Tamoxifen in breast cancer treatment including mechanisms and side-effects. Finally, we discuss in detail the exciting prospects that lie ahead. PMID:23711794

  19. Successful use of agomelatine in the treatment of major depression in a woman taking tamoxifen: a case report.

    PubMed

    De Berardis, Domenico; Brucchi, Maurizio; Serroni, Nicola; Valchera, Alessandro; Fornaro, Michele; Mazza, Monica; Martinotti, Giovanni; Di Giannantonio, Massimo

    2014-01-01

    The selective estrogen receptor modulator, tamoxifen, is extensively used for the endocrine treatment of all stages of hormone receptor-positive breast cancer. Tamoxifen is a mainly inactive prodrug, necessitating metabolism by the cytochrome P450 (CYP450) pathway, predominantly the Cytochrome P450 2D6 (CYP2D6), into the active metabolites 4-hydroxytamoxifen and, in particular, endoxifen to achieve its therapeutic effect. As several women treated with tamoxifen may experience depressive symptoms or may have a previous or actual major depressive episode with ongoing antidepressant treatment or need for a new-onset therapy, the coprescription of an antidepressant drug may be particularly problematic as several antidepressants are potent CYP2D6-inhibiting drugs. We herein report a case of a patient with major depression and concurrent tamoxifen therapy successfully treated with agomelatine monotherapy. PMID:24434530

  20. Differential Response to α-Oxoaldehydes in Tamoxifen Resistant MCF-7 Breast Cancer Cells

    PubMed Central

    Nass, Norbert; Brömme, Hans-Jürgen; Hartig, Roland; Korkmaz, Sevil; Sel, Saadettin; Hirche, Frank; Ward, Aoife; Simm, Andreas; Wiemann, Stefan; Lykkesfeldt, Anne E.; Roessner, Albert; Kalinski, Thomas

    2014-01-01

    Tamoxifen is the standard adjuvant endocrine therapy for estrogen-receptor positive premenopausal breast cancer patients. However, tamoxifen resistance is frequently observed under therapy. A tamoxifen resistant cell line has been generated from the estrogen receptor positive mamma carcinoma cell line MCF-7 and was analyzed for putative differences in the aldehyde defence system and accumulation of advanced glycation end products (AGE). In comparison to wt MCF-7 cells, these tamoxifen resistant cells were more sensitive to the dicarbonyl compounds glyoxal and methylglyoxal and displayed increased caspase activity, p38-MAPK- and IκBα-phosphorylation. However, mRNA accumulation of the aldehyde- and AGE-defence enzymes glyoxalase-1 and -2 (GLO1, GLO2) as well as fructosamine-3-kinase (FN3K) was not significantly altered. Tamoxifen resistant cells contained less free sulfhydryl-groups (glutathione) suggesting that the increased sensitivity towards the dicarbonyls was due to a higher sensitivity towards reactive oxygen species which are associated with dicarbonyl stress. To further analyse, if these data are of more general importance, key experiments were replicated with tamoxifen resistant MCF-7 cell lines from two independent sources. These cell lines were also more sensitive to aldehydes, especially glyoxal, but were different in their cellular signalling responses to the aldehydes. In conclusion, glyoxalases and other aldehyde defence enzymes might represent a promising target for the therapy of tamoxifen resistant breast cancers. PMID:24983248

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

    PubMed Central

    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

    2014-01-01

    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. PMID:24975596

  2. 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. PMID:21892704

  3. 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

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

    PubMed

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

    2015-12-01

    Tamoxifen is a cornerstone component of adjuvant endocrine therapy for patients with hormone-receptor-positive breast cancer. Its significant adverse effects include uterine hyperplasia, polyps, and increased risk of endometrial cancer. However, the underlying molecular mechanism remains unclear. Excessive angiogenesis, a hallmark of tumorigenesis, is a result of disrupted balance between pro- and anti-angiogenic factors. VEGF is a pro-angiogenic factor shown to be elevated by tamoxifen in the uterus. Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor that suppresses strong pro-angiogenic factors, such as VEGF. Our aim was to investigate whether angiogenic balance plays a role in tamoxifen-induced uterine pathologies, elucidate the molecular impairment in that network, and explore potential intervention to offset the proposed imbalance elicited by tamoxifen. Using in vivo mouse models, we demonstrated that tamoxifen induced a dose-dependent shift in endogenous uterine angiogenic balance favoring VEGF over PEDF. Treatment with recombinant PEDF (rPEDF) abrogated tamoxifen-induced uterine hyperplasia and VEGF elevation, resulting in reduction of blood vessels density. Exploring the molecular mechanism revealed that tamoxifen promoted survival and malignant transformation pathways, whereas rPEDF treatment prevents these changes. Activation of survival pathways was decreased, demonstrated by reduction in AKT phosphorylation concomitant with elevation in JNK phosphorylation. Estrogen receptor-α and c-Myc oncoprotein levels were reduced. Our findings provide novel insight into the molecular mechanisms tamoxifen induces in the uterus, which may become the precursor events of subsequent endometrial hyperplasia and cancer. We demonstrate that rPEDF may serve as a useful intervention to alleviate the risk of tamoxifen-induced endometrial pathologies. PMID:26450919

  5. 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

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

    PubMed

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

    2014-11-01

    A selective and accurate analytical method is needed to quantify tamoxifen and its phase I metabolites in a prospective clinical protocol, for evaluation of pharmacokinetic parameters of tamoxifen and its metabolites in adjuvant treatment of breast cancer. The selectivity of the analytical method is a fundamental criteria to allow the quantification of the main active metabolites (Z)-isomers from (Z)'-isomers. An UPLC-MS/MS method was developed and validated for the quantification of (Z)-tamoxifen, (Z)-endoxifen, (E)-endoxifen, Z'-endoxifen, (Z)'-endoxifen, (Z)-4-hydroxytamoxifen, (Z)-4'-hydroxytamoxifen, N-desmethyl tamoxifen, and tamoxifen-N-oxide. The validation range was set between 0.5ng/mL and 125ng/mL for 4-hydroxytamoxifen and endoxifen isomers, and between 12.5ng/mL and 300ng/mL for tamoxifen, tamoxifen N-desmethyl and tamoxifen-N-oxide. The application to patient plasma samples was performed. PMID:25173109

  7. Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update

    PubMed Central

    Burstein, Harold J.; Temin, Sarah; Anderson, Holly; Buchholz, Thomas A.; Davidson, Nancy E.; Gelmon, Karen E.; Giordano, Sharon H.; Hudis, Clifford A.; Rowden, Diana; Solky, Alexander J.; Stearns, Vered; Winer, Eric P.; Griggs, Jennifer J.

    2014-01-01

    Purpose To update the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment, particularly adjuvant tamoxifen. Methods ASCO convened the Update Committee and conducted a systematic review of randomized clinical trials from January 2009 to June 2013 and analyzed three historical trials. Guideline recommendations were based on the Update Committee's review of the evidence. Outcomes of interest included survival, disease recurrence, and adverse events. Results This guideline update reflects emerging data on duration of tamoxifen treatment. There have been five studies of tamoxifen treatment beyond 5 years of therapy. The two largest studies with longest reported follow-up show a breast cancer survival advantage with 10-year durations of tamoxifen use. In addition to modest gains in survival, extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer. Recommendations Previous ASCO guidelines recommended treatment of women who have hormone receptor–positive breast cancer and are premenopausal with 5 years of tamoxifen, and those who are postmenopausal a minimum of 5 years of adjuvant therapy with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor (in sequence). If women are pre- or perimenopausal and have received 5 years of adjuvant tamoxifen, they should be offered 10 years total duration of tamoxifen. If women are postmenopausal and have received 5 years of adjuvant tamoxifen, they should be offered the choice of continuing tamoxifen or switching to an aromatase inhibitor for 10 years total adjuvant endocrine therapy. PMID:24868023

  8. Tamoxifen precipitation of familial hypertriglyceridaemia: a rare cause of acute pancreatitis.

    PubMed

    Wadood, Ali; Chesner, Robert; Mirza, Mehboob; Zaman, Shafquat

    2016-01-01

    Drug-induced pancreatitis is uncommon, and is estimated to account for between 0.1% and 5% of cases. Tamoxifen is commonly used in the management of oestrogen receptor-positive breast cancer. We present a rare case of tamoxifen-related hyperlipidaemia resulting in repeated episodes of pancreatitis, which, to the best of our knowledge, has only been documented a few times in the literature. A 36-year-old woman with familial hypertriglyceridaemia presented with recurrent episodes of abdominal pain, modest increases in serum amylase levels and normal liver function tests. The patient had recently been diagnosed with breast carcinoma and was managed with wide local excision (WLE), adjuvant radiotherapy and tamoxifen. On each admission, the patient's symptoms were confirmed either biochemically and/or radiologically. Analysis of the case led to a diagnosis of precipitation of familial hypertriglyceridaemia from tamoxifen use resulting in pancreatitis. Management was altered with tamoxifen cessation and initiation of second-line hormonal therapy. Tamoxifen use needs consideration, especially in those with familial hyperlipidaemia. PMID:27489062

  9. Deciphering the Nongenomic, Mitochondrial Toxicity of Tamoxifens As Determined by Cell Metabolism and Redox Activity.

    PubMed

    Theodossiou, Theodossis Athanassios; Wälchli, Sébastien; Olsen, Cathrine Elisabeth; Skarpen, Ellen; Berg, Kristian

    2016-01-15

    Tamoxifen is not only considered a very potent chemotherapeutic adjuvant for estrogen receptor positive breast cancers but also a very good chemo-preventive drug. Recently, there has been a rising amount of evidence for a nongenomic cytotoxicity of tamoxifen, even in estrogen receptor negative cells, which has greatly confounded researchers. Clinically, the side effects of tamoxifen can be very serious, ranging from liver steatosis to cirrhosis, tumorigenesis, or onset of porphyrias. Herein, we deciphered the nongenomic, mitochondrial cytotoxicity of tamoxifen in estrogen receptor positive MCF7 versus triple-negative MDA-MB-231 cells, employing the mitochondrial complex III quinoloxidizing-center inhibitor myxothiazol. We showed a role for hydroxyl-radical-mediated lipid peroxidation, catalyzed by iron, stemming from the redox interactions of tamoxifen quinoid metabolites with complex III, resulting in Fenton-capable reduced quinones. The role of tamoxifen semiquinone species in mitochondrial toxicity was also shown together with evidence of mitochondrial DNA damage. Tamoxifen caused an overall metabolic (respiratory and glycolytic) rate decrease in the Pasteur type MCF cells, while in the Warburg type MDA-MB-231 cells the respiratory rate was not significantly affected and the glycolytiv rate was significantly boosted. The nongenomic cytotoxicity of tamoxifens was hence associated with the metabolic phenotype and redox activity of the cells, as in the present paradigm of Pasteur MCF7s versus Warburg MDA-MB-231 cells. Our present findings call for caution in the use of the drugs, especially as a chemopreventive and/or in cases of iron overload diseases. PMID:26569462

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

    PubMed

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

    2014-03-01

    Tamoxifen is a triphenylethylene nonsteroidal estrogen receptor (ER) antagonist used worldwide as an adjuvant hormone therapeutic agent in the treatment of breast cancer. However, the molecular mechanism of tamoxifen-induced cytotoxicity in non-small cell lung cancer (NSCLC) cells has not been identified. Thymidine phosphorylase (TP) is an enzyme of the pyrimidine salvage pathway which is upregulated in cancers. In this study, tamoxifen treatment inhibited cell survival in two NSCLC cells, H520 and H1975. Treatment with tamoxifen decreased TP mRNA and protein levels through AKT inactivation. Furthermore, expression of constitutively active AKT (AKT-CA) vectors significantly rescued the decreased TP protein and mRNA levels in tamoxifen-treated NSCLC cells. In contrast, combination treatment with PI3K inhibitors (LY294002 or wortmannin) and tamoxifen further decreased the TP expression and cell viability of NSCLC cells. Knocking down TP expression by transfection with small interfering RNA of TP enhanced the cytotoxicity and cell growth inhibition of tamoxifen. Erlotinib (Tarceva, OSI-774), an orally available small molecular inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is approved for clinical treatment of NSCLC. Compared to a single agent alone, tamoxifen combined with erlotinib resulted in cytotoxicity and cell growth inhibition synergistically in NSCLC cells, accompanied with reduced activation of phospho-AKT and phospho-ERK1/2, and reduced TP protein levels. These findings may have implications for the rational design of future drug regimens incorporating tamoxifen and erlotinib for the treatment of NSCLC. PMID:24447935

  11. 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. |

  12. 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

  13. 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

  14. [Adjuvant endocrine therapy in breast cancer. Management of early-risk relapse].

    PubMed

    Chahine, Georges; Howayek, Mireille; Atallah, David

    2009-01-01

    The goal of adjuvant endocrine therapy for early breast cancer is to prolong overall survival and improve the quality of life of patients. Studies on breast cancer show an early peak of recurrence at two years after surgery and distant recurrences that are responsible for a significant reduction in overall survival. Tamoxifen has been the standard of adjuvant endocrine therapy in breast cancer for years, however only about half of relapses are prevented and there is an early occurrence of serious adverse events due to agonistic estrogenic activity of tamoxifen, such as an increase in the risk of endometrial hyperplasia and venous thromboembolism. The use of aromatase inhibitors is changing this standard with studies covering various clinical settings. They have shown a benefit in many situations, such as an extension of endocrine therapy by tamoxifen, sequential hormonotherapy or up-front adjuvant therapy with aromatase inhibitors. PMID:19623889

  15. Clinical Relevance of CYP2D6 Genetics for Tamoxifen Response in Breast Cancer

    PubMed Central

    Brauch, Hiltrud; Schroth, Werner; Eichelbaum, Michel; Schwab, Matthias; Harbeck, Nadia

    2008-01-01

    Summary Tamoxifen is a standard endocrine therapy for the prevention and treatment of steroid hormone receptor-positive breast cancer. Tamoxifen requires enzymatic activation by CYP 450 enzymes for the formation of clinically relevant metabolites, 4-OH-tamoxifen and endoxifen, which both have a greater affinity to the estrogen receptor and ability to inhibit cell proliferation when compared to the parent drug. CYP2D6 is the key enzyme in this biotransformation, and recent mechanistic, pharmacologic, and clinical pharmacogenetic evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors influence plasma concentrations of active tamoxifen metabolites and outcome of patients treated with adjuvant tamoxifen. Particularly, non-functional (poor metabolizer) and severely impaired (intermediate metabolizer) CYP2D6 variants are associated with higher recurrence rates. Accordingly, CYP2D6 genotyping prior to treatment for prediction of metabolizer status and outcome may open new avenues for the individualization of endocrine treatment choice and benefit. Moreover, strong CYP2D6 inhibitors such as the selective serotonin reuptake inhibitor paroxetine should be avoided as co-medication. PMID:20824020

  16. 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

  17. [Laparoscopic surgery and adjuvant therapy for colon cancer].

    PubMed

    Kubicka, Stefan; Geissler, Michael; Bruch, Hans-Peter; Trarbach, Tanja

    2009-01-01

    At present, about 10% of all oncological procedures in the colon are carried out laparoscopically. Acceptance is increasing. After successful R0 resection, the rule for stage III patients is: adjuvant therapy is indicated regardless of age. Regimens containing oxaliplatin should be used. If there are contraindications for oxaliplatin, then fluoropyrimidine monotherapy is indicated, with oral fluoropyrimidines (capecitabine) being given precedence over infusional schemes. The use of 5-FU bolus regimens is regarded as obsolete. For stage II, the following applies: If an adjuvant chemotherapy is planned in these patients on the basis of the QUASAR data, then fluoropyrimidine monotherapy (e. g. capecitabine) can be given. Since patients whose tumours show a high frequency of microsatellite instability (MSI) do not benefit from a fluoropyrimidine monotherapy, the MSI status should be determined before choosing therapy. PMID:19546595

  18. 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

  19. 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.

  20. Personalized medicine in breast cancer: tamoxifen, endoxifen, and CYP2D6 in clinical practice.

    PubMed

    Ruddy, Kathryn J; Desantis, Stephen D; Gelman, Rebecca S; Wu, Alan H B; Punglia, Rinaa S; Mayer, Erica L; Tolaney, Sara M; Winer, Eric P; Partridge, Ann H; Burstein, Harold J

    2013-10-01

    Tamoxifen is metabolized into endoxifen, a potent antagonist of the estrogen receptor, in part through cytochrome p450 (CYP) 2D6. Genotypic variation in CYP2D6 affects endoxifen levels, and some have argued that patients who do not efficiently metabolize tamoxifen might wish to consider alternative hormonal treatments. This study evaluated an algorithm in which endoxifen levels and CYP2D6 genotypes were used to make hormonal therapy recommendations for patients on adjuvant tamoxifen for breast cancer. Patients with stage I-III breast cancer who had been taking adjuvant tamoxifen for 8-56 weeks were eligible. At enrollment, baseline whole blood and serum were sent for genotyping by Amplichip and endoxifen measurement, respectively, and endoxifen levels were also measured 3 weeks later. Results were returned to oncologists along with an algorithm-generated treatment recommendation. The algorithm recommended that participants with poor metabolizer genotype and/or baseline endoxifen level <6 ng/mL consider alternative endocrine therapy. A medical record review evaluated actual treatment decisions. Of 99 patients on study, 18 (18 %) had findings that triggered algorithm-based recommendations to consider a change in endocrine therapy due to endoxifen <6 ng/mL (all 18 patients) and/or poor metabolizer CYP2D6 genotype (2 of the 18). Endoxifen levels were ≥6 ng/mL in four of them 3 weeks later. Seven (39 % of 18) switched to a different treatment (one based on toxicity, not the algorithm). Hot flash burden was not found to be significantly associated with endoxifen <6 ng/mL or genotype. Prospective testing of tamoxifen metabolism as gauged by CYP2D6 genotype and serum endoxifen levels is feasible. Future studies of tamoxifen metabolism and efficacy should consider including measurement of serial endoxifen levels. Although clinical evidence at present is insufficient to warrant routine CYP2D6 or endoxifen testing, some clinicians and patients did utilize this

  1. 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

  2. Continuous tamoxifen treatment in asymptomatic, postmenopausal breast cancer patients does not cause aggravation of endometrial pathologies.

    PubMed

    Cohen, I; Tepper, R; Rosen, D J; Shapira, J; Cordoba, M; Dror, Y; Altaras, M; Beyth, Y

    1994-10-01

    Adjuvant tamoxifen therapy for breast cancer patients has been found to be associated with various endometrial pathologic conditions, including endometrial cancer. This preliminary case control study evaluated whether prolonged and continuous exposure to tamoxifen in the menopause may aggravate existing endometrial pathologies. Two vaginal ultrasound evaluations of endometrial thickness and histologic findings of two endometrial biopsies, performed 18 months apart, were evaluated for 25 asymptomatic, postmenopausal breast cancer patients who were continuously treated with tamoxifen. In the first endometrial biopsy, 4 patients (16.0%) were found to have endometrial pathologies: 2 patients had proliferative endometrium, 1 had hyperplastic endometrium, and 1 had an endometrial polyp. In the second endometrial biopsy, none of these patients showed any endometrial pathologies. Another patient (4.0%) with no endometrial pathology in the first visit had endometrial hyperplasia in the second visit. None of the patients developed endometrial cancer, and generally there was no increase in ultrasonographically-measured endometrial widths. The results of this preliminary study may suggest that there is no increased risk of development of endometrial pathologies during an additional 18 months of continuous tamoxifen therapy nor is there aggravation of already existing endometrial pathologies. PMID:7959255

  3. Adjuvant treatment

    PubMed Central

    Sultana, Asma; Neoptolemos, John

    2006-01-01

    Exocrine pancreatic cancer (pancreatic ductal adenocarcinoma) is one of the leading causes of cancer deaths in the western world, accounting for 5% of all cancer-related deaths. Only a small percentage of patients with pancreatic cancer are able to undergo potentially curative resection, even in specialized centres, and prognosis remains poor after successful surgery. Over the last few years efforts have been directed towards the development of adjuvant therapies in attempts to improve outcome. The main trials of adjuvant chemotherapy, chemoradiotherapy and chemoradiotherapy with follow-on chemotherapy are described in this paper, followed by the results of the ESPAC-1 trial and the status of ESPAC-2 and -3 trials. PMID:18333088

  4. Aromatase inhibitor plus ovarian suppression as adjuvant therapy in premenopausal women with breast cancer

    PubMed Central

    Figg, William D; Cook, Katherine; Clarke, Robert

    2014-01-01

    The goal of adjuvant hormonal therapy for breast cancer is to prevent recurrence by eradicating micrometastatic disease. Recent studies have shown that the use of aromatase inhibitors (AIs) as adjuvant therapy improves outcomes for postmenopausal women with estrogen receptor (ER)-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone. The research question has been raised whether AIs would have similar improvements in disease-free survival (DFS) in premenopausal women with ER-positive breast cancer. Combining 2 phase 3 clinical trials (n = 4,690), Pagani and colleagues randomized premenopausal women with ER-positive early breast cancer to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 y. After a median follow-up of 68 months, DFS was 91.1% in the AI group and 87.3% in the tamoxifen group. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. PMID:25535893

  5. Meta-analysis of breast cancer outcome and toxicity in adjuvant trials of aromatase inhibitors in postmenopausal women.

    PubMed

    Aydiner, Adnan

    2013-04-01

    The present meta-analysis examines randomized trials of third-generation aromatase inhibitors (AIs) as alternatives to tamoxifen in three treatment settings: monotherapy, sequenced therapy and extended therapy. Eleven randomized controlled trials (RCTs) were chosen based on their similarity in terms of study design and included 34,070 post-menopausal women who had undergone surgery for estrogen-sensitive early breast cancer. DFS was significantly improved by AI monotherapy (Hazard Ratio (HR): 0.89, p = 0.001), sequenced therapy (HR: 0.7, p < 0.00001) and extended therapy (HR: 0.62, p < 0.00001). All of the patients benefited significantly from sequenced therapy (HR: 0.81, p = 0.003), and hormone receptor-positive patients benefited from AI monotherapy (HR = 0.92, p = 0.046) with respect to OS. AI monotherapy conferred significantly lower risks for thromboembolic events (OR = 0.61; p < 0.001) and endometrial cancer (OR = 0.26; p < 0.001) compared with tamoxifen monotherapy; however, there was a greater risk of cardiovascular events (OR = 1.20; p = 0.030). Sequenced therapy was also superior in terms of endometrial cancer but was inferior with respect to fractures, thromboembolic and cardiovascular events. PMID:23462682

  6. Tamoxifen

    MedlinePlus

    ... carcinoma in situ (DCIS; a type of breast cancer that does not spread outside of the milk duct where it forms) and who have been treated with surgery and radiation. It is used to reduce the risk of breast cancer in women who are at high risk for ...

  7. 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

  8. Tamoxifen-induced hypertriglyceridemia causing acute pancreatitis

    PubMed Central

    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

  9. 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

  10. 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

  11. 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

  12. [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

  13. 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

  14. 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.

  15. Modification of sphingolipid metabolism by tamoxifen and N-desmethyltamoxifen in acute myelogenous leukemia – Impact on enzyme activity and response to cytotoxics

    PubMed Central

    Morad, Samy A. F.; Tan, Su-Fern; Feith, David J.; Kester, Mark; Claxton, David F.; Loughran, Thomas P.; Barth, Brian M.; Fox, Todd E.; Cabot, Myles C.

    2015-01-01

    The triphenylethylene antiestrogen, tamoxifen, can be an effective inhibitor of sphingolipid metabolism. This off-target activity makes tamoxifen an interesting ancillary for boosting the apoptosis-inducing properties of ceramide, a sphingolipid with valuable tumor censoring activity. Here we show for the first time that tamoxifen and metabolite, N –desmethyltamoxifen (DMT) block ceramide glycosylation and inhibit ceramide hydrolysis (by acid ceramidase, AC) in human acute myelogenous leukemia (AML) cell lines and in AML cells derived from patients. Tamoxifen (1-10 μM) inhibition of AC in AML cells was accompanied by decreases in AC protein expression. Tamoxifen also depressed expression and activity of sphingosine kinase 1 (SphK1), the enzyme catalyzing production of mitogenic sphingosine 1-phosphate (S1-P). Results from mass spectroscopy showed that tamoxifen and DMT, i ) increased the levels of endogenous C16:0- and C24:1 ceramide molecular species, ii) nearly totally halted production of respective glucosylceramide (GC) molecular species, iii ) drastically reduced levels of sphingosine ( to 9% of control), and iv ) reduced levels of S1-P by 85%, in vincristine-resistant HL-60/VCR cells. Co-administration of tamoxifen with either N-(4-hydroxyphenyl)retinamide (4-HPR), a ceramide-generating retinoid, or a cell-deliverable form of ceramide, C6-ceramide, resulted in marked decreases in HL-60/VCR cell viability that far exceeded single agent potency. Combination treatments resulted in synergistic apoptotic cell death as gauged by increased Annexin V binding and DNA fragmentation and activation of caspase-3. These results show the versatility of adjuvant triphenylethylene with ceramide-centric therapies for magnifying therapeutic potential in AML. Such drug regimens could serve as effective strategies, even in the multidrug resistant setting. PMID:25769964

  16. 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

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

    PubMed

    Yeh, Wei-Lan; Lin, Hui-Yi; Wu, Hung-Ming; Chen, Dar-Ren

    2014-01-01

    Tamoxifen has long been used and still is the most commonly used endocrine therapy for treatment of both early and advanced estrogen receptor-positive breast cancer in pre- and post-menopause women. Tamoxifen exerts its cytotoxic effect primarily through cytostasis which is associated with the accumulation of cells in the G0/G1 phase of the cell cycle. Apoptotic activity can also be exerted by tamoxifen which involves cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP-ribose polymerase (PARP). Down-regulation of anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulation of pro-apoptotic proteins Bax and Bak have also been observed. In addition, stress response protein of GRP 94 and GRP 78 have also been induced by tamoxifen in our study. However, side effects occur during tamoxifen treatment in breast cancer patients. Researching into combination regimen of tamoxifen and drug(s) that relieves tamoxifen-induced hot flushes is important, because drug interactions may decrease tamoxifen efficacy. Risperidone has been shown to be effective in reducing or eliminating hot flushes on women with hormonal variations. In this present study, we demonstrated that combination of tamoxifen with risperidone did not interfered tamoxifen-induced cytotoxic effects in both in vitro and in vivo models, while fluoxetine abrogated the effects of tamoxifen. This is the first paper suggesting the possibility of combination treatment of tamoxifen with risperidone in breast cancer patients, providing a conceivable resolution of tamoxifen-induced side effects without interfering the efficacy of tamoxifen against breast cancer. PMID:24886861

  18. 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

  19. 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

  20. 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. PMID

  1. 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

  2. Tailored Tamoxifen Treatment for Breast Cancer Patients: A Perspective.

    PubMed

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

    2015-08-01

    Tamoxifen, an endocrine agent, is widely used in the treatment of estrogen receptor-positive breast cancer. It has greatly reduced disease recurrence and mortality rates of breast cancer patients, however, not all patients benefit from tamoxifen treatment because in approximately 25% to 30% of the patients the disease recurs. Many researchers have sought to find factors associated with endocrine treatment outcome in the past years, however, this quest has not been finished. In this article, we focus on a factor that might influence outcome of tamoxifen treatment: interpatient variability in tamoxifen pharmacokinetics. In recent years it has become clear that tamoxifen undergoes extensive metabolism and that some of the formed metabolites are much more pharmacologically active than tamoxifen itself. Despite the wide interpatient variability in tamoxifen pharmacokinetics and pharmacodynamics, all patients receive a standard dose of 20 mg tamoxifen per day. Different approaches can be pursued to individualize tamoxifen dosing: genotyping, phenotyping, and therapeutic drug monitoring. Therapeutic drug monitoring seems to be the most direct and promising approach, however, further clinical research is warranted to establish the added value of individual dosing in tamoxifen treatment optimization. PMID:25997856

  3. 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

  4. Tamoxifen in men: a review of adverse events.

    PubMed

    Wibowo, E; Pollock, P A; Hollis, N; Wassersug, R J

    2016-09-01

    Tamoxifen is an off-label option to treat men for breast cancer, infertility, and idiopathic gynecomastia. Lately, tamoxifen has been proposed as a treatment to prevent gynecomastia in prostate cancer patients receiving antiandrogen therapy. We reviewed the adverse events (AEs) reported in studies of men prescribed tamoxifen for these conditions to better understand its side-effect profile. We searched PubMed for randomized controlled trials (RCTs) that included safety data of tamoxifen treatment in men with prostate cancer, breast cancer, infertility, and idiopathic gynecomastia. Non-RCTs were also reviewed. The results demonstrate that the AE profile in tamoxifen-treated male populations varied. Excluding breast events, gastrointestinal, and cardiovascular problems were the most commonly reported AEs in prostate cancer patients, whereas more psychiatric disorders were reported in male breast cancer patients. Few AEs have been documented in men receiving tamoxifen for infertility and idiopathic gynecomastia. Less than 5% of men withdrew from tamoxifen therapy because of toxicity. This suggests that for most men, tamoxifen is well-tolerated. Of those who discontinued tamoxifen, the majority were male breast cancer patients, and cardiovascular events were the most common reason for stopping tamoxifen treatment. Unfortunately, in many cases, the reasons for withdrawing tamoxifen were unspecified. Based on the available evidence, tamoxifen's AE profile appears to vary depending upon which male population is treated. Also, the frequency at which AEs occur varies - less AEs in men with infertility and idiopathic gynecomastia compared to men with prostate cancer or breast cancer. Long-term studies that rigorously document the side-effect profile of tamoxifen in men are lacking. PMID:27152880

  5. 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

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

    PubMed Central

    Phillips, Kelly-Anne; Milne, Roger L.; Rookus, Matti A.; Daly, Mary B.; Antoniou, Antonis C.; Peock, Susan; Frost, Debra; Easton, Douglas F.; Ellis, Steve; Friedlander, Michael L.; Buys, Saundra S.; Andrieu, Nadine; Noguès, Catherine; Stoppa-Lyonnet, Dominique; Bonadona, Valérie; Pujol, Pascal; McLachlan, Sue Anne; John, Esther M.; Hooning, Maartje J.; Seynaeve, Caroline; Tollenaar, Rob A.E.M.; Goldgar, David E.; Beth Terry, Mary; Caldes, Trinidad; Weideman, Prue C.; Andrulis, Irene L.; Singer, Christian F.; Birch, Kate; Simard, Jacques; Southey, Melissa C.; Olsson, Håkan L.; Jakubowska, Anna; Olah, Edith; Gerdes, Anne-Marie; Foretova, Lenka; Hopper, John L.

    2013-01-01

    Purpose To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Methods Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up. Results Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases). Conclusion This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses. PMID:23918944

  7. Pharmacogenomics toward personalized tamoxifen therapy for breast cancer.

    PubMed

    Zembutsu, Hitoshi

    2015-01-01

    Tamoxifen has been used not only for the treatment or prevention of recurrence in patients with estrogen receptor positive breast cancers but also for recurrent breast cancer. Because CYP2D6 is known to be an important enzyme responsible for the generation of the potent tamoxifen metabolite, 'endoxifen', lots of studies reported that genetic variation which reduced its enzyme activity were associated with poor clinical outcome of breast cancer patients treated with tamoxifen. However, there are some discrepant reports questioning the association between CYP2D6 genotype and clinical outcome after tamoxifen therapy. Dose-adjustment study of tamoxifen based on CYP2D6 genotypes provides the evidence that dose adjustment is useful for the patients carrying reduced or null allele of CYP2D6 to maintain the effective endoxifen level. This review describes critical issues in pharmacogenomic studies as well as summarizes the results of the association of CYP2D6 genotype with tamoxifen efficacy. PMID:25712191

  8. The bioavailability of Tamoplex (tamoxifen). Part 1. A pilot study.

    PubMed

    McVie, J G; Simonetti, G P; Stevenson, D; Briggs, R J; Guelen, P J; de Vos, D

    1986-08-01

    Tamoxifen and N-desmethyltamoxifen plasma concentrations were found to be similar after a first single dose and during two months therapy with Tamoplex or Nolvadex in groups of 6 and 8 patients, respectively. Single dose absorption results in 10 healthy male volunteers demonstrated bioequivalence of Tamoplex and Nolvadex 10 mg tablets. A large interindividual variation in tamoxifen absorption data was observed, probably related to the dominating metabolic clearance of tamoxifen. PMID:3747644

  9. The effect of tamoxifen on the genital tract

    PubMed Central

    Ascher, Susan M.

    2008-01-01

    Abstract Tamoxifen is a selective estrogen receptor modulator (SERM) that is widely used in the treatment of patients with breast cancer and for chemoprophylaxis in high risk women. Tamoxifen results in a spectrum of abnormalities involving the genital tract, the most significant being an increased incidence of endometrial cancer and uterine sarcoma. This article reviews the effects of tamoxifen on the genital tract and the strengths and weaknesses of various imaging modalities for evaluating the endometrium. PMID:18603495

  10. Trends in vaccine adjuvants.

    PubMed

    Schijns, Virgil E J C; Lavelle, Ed C

    2011-04-01

    Adjuvants are essential components of most clinically used vaccines. This is because the majority of nonliving vaccines are relatively poor inducers of adaptive immunity unless effective adjuvants are co-administered. Aluminum salts (alum) have been used as adjuvants with great success for almost a century and have been particularly effective at promoting protective humoral immunity. However, alum is not optimally effective for diseases where cell-mediated immunity is required for protection. Furthermore, adjuvants including oil-in-water emulsions have shown improved efficacy for avian influenza protection suggesting that even for diseases where humoral immunity can confer protection, there is scope for developing improved adjuvants. There have been major developments in antigen discovery over the past decade, which has accelerated the vaccine development process for new indications and this demands a new generation of adjuvants that can drive and specifically direct the desired immune responses. A number of systems are under investigation that combine different types of adjuvants into specific formulations with greater activity. Additionally, targeting of vaccines to specific immune cells shows great promise. In the case of cancer and chronic infectious diseases, it may be difficult to develop effective vaccines without blocking immune regulatory pathways, which impede cell-mediated responses. However, increased understanding of immunology and particularly the innate immune system is informing vaccine adjuvant research and consequently driving the development of novel and specifically directed vaccine adjuvant strategies. In this article we address the importance of adjuvants in vaccine development, the known mode of action of specific adjuvants and recent developments in this important field. PMID:21506650

  11. 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

  12. Capecitabine Monotherapy: Review of Studies in First-Line HER-2-Negative Metastatic Breast Cancer

    PubMed Central

    Kaufmann, Manfred; Siedentopf, Friederike; Dalivoust, Philippe; Debled, Marc; Robert, Nicholas J.; Harbeck, Nadia

    2012-01-01

    The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2–negative MBC. PMID:22418569

  13. [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. PMID:22129866

  14. 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.

  15. Estradiol and tamoxifen interaction at receptor sites at 37 C.

    PubMed

    Fishman, J H

    1983-09-01

    Mature rat uterine cytosol was pretreated with dextran-coated charcoal at 0 C for 2 h. This renders the subsequently formed estradiol-receptor complex thermostable at 37 C and also uncovers antiestrogen binding sites, possibly by removing an endogenous ligand. A sharp distinction is found between tamoxifen and estradiol as receptor ligands in pretreated cytosols in that tamoxifen will inhibit estradiol binding, on incubation at 37 C, only if dithiothreitol (DTT) had been included in the pretreatment solution. The presence of tamoxifen as the sole ligand in cytosol pretreated in the presence of DTT does not protect the estradiol receptor from thermal inactivation and following 37 C incubation tamoxifen is found bound exclusively to antiestrogen binding sites. Incubating the cytosol at 37 C with an equimolar mixture of estradiol and tamoxifen results in a very large increase in receptor-bound estradiol. This effect is attributed to the presence of tamoxifen complexed with antiestrogen sites. Tamoxifen in such equimolar ligand mixture binds to antiestrogen sites and is excluded from receptor sites by the estradiol, whose affinity for these sites is much greater than that of tamoxifen. PMID:6191968

  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. Effects of Pharmacogenetics on the Pharmacokinetics and Pharmacodynamics of Tamoxifen.

    PubMed

    de Vries Schultink, Aurelia H M; Zwart, Wilbert; Linn, Sabine C; Beijnen, Jos H; Huitema, Alwin D R

    2015-08-01

    The antiestrogenic drug tamoxifen is widely used in the treatment of estrogen receptor-α-positive breast cancer and substantially decreases recurrence and mortality rates. However, high interindividual variability in response is observed, calling for a personalized approach to tamoxifen treatment. Tamoxifen is bioactivated by cytochrome P450 (CYP) enzymes such as CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5, resulting in the formation of active metabolites, including 4-hydroxy-tamoxifen and endoxifen. Therefore, polymorphisms in the genes encoding these enzymes are proposed to influence tamoxifen and active tamoxifen metabolites in the serum and consequently affect patient response rates. To tailor tamoxifen treatment, multiple studies have been performed to clarify the influence of polymorphisms on its pharmacokinetics and pharmacodynamics. Nevertheless, personalized treatment of tamoxifen based on genotyping has not yet met consensus. This article critically reviews the published data on the effect of various genetic polymorphisms on the pharmacokinetics and pharmacodynamics of tamoxifen, and reviews the clinical implications of its findings. For each CYP enzyme, the influence of polymorphisms on pharmacokinetic and pharmacodynamic outcome measures is described throughout this review. No clear effects on pharmacokinetics and pharmacodynamics were seen for various polymorphisms in the CYP encoding genes CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. For CYP2D6, there was a clear gene-exposure effect that was able to partially explain the interindividual variability in plasma concentrations of the pharmacologically most active metabolite endoxifen; however, a clear exposure-response effect remained controversial. These controversial findings and the partial contribution of genotype in explaining interindividual variability in plasma concentrations of, in particular, endoxifen, imply that tailored tamoxifen treatment may not be fully realized through pharmacogenetics of

  18. AB081. Effects of combination therapy of Tamoxifen, L-carnitine and daily PDE5 inhibitors in the Peyronie’s disease

    PubMed Central

    Kang, Jae Il; Park, Tae Yong; Jeong, Hyeong Guk; Park, Jong Jin; Chae, Ji Yun; Kim, Jong Wook; Oh, Mi Mi; Park, Hong Seok; Kim, Je Jong; Moon, Du Geon

    2016-01-01

    Objective This study was designed to evaluate the efficacy of combination therapy of Tamoxifen, L-carnitine and daily PDE5 inhibitors and to compare with Potassium para-aminobenzoate (Potaba) monotherapy in the medical treatment of Peyronie’s disease. Methods From January 2011 to December 2014, a total of 104 patients with Peyronie’s disease enrolled in this study. Sixty-eight patients were treated with Tamoxifen 20 mg and Acetyl L-carnitine 330 mg twice a daily in addition to daily PDE5 inhibitors (Tadalafil 5 mg once daily) combination therapy (Group 1), while thirty-four patients were treated with Potassium para-aminobenzoate 12 g daily (Group 2), Pain on erection, impossibility of intercourse, plaque size, penile curvature and IIEF-5 were assessed. Plaque volume was assessed by penile ultrasonography. Results Both groups showed resolution of pain and intercourse satisfaction after treatment. The pre-treatment plaque sizes of both groups were 17.1±7.2, 17.0±5.0 mm, respectively. After treatment, those parameters significantly reduced to 13.2±5.6, 16.2±5.3 mm. In group 1, combination therapy significantly improved the angle of penile curvature, plaque size, and IIEF (P value <0.05). In group 2, the size of the plaque, penile curvature and IIEF were improved after Potassium para-aminobenzoate monotherapy. However, no significant differences were observed. Conclusion Statistically significant improvement in intercourse satisfaction, plaque size, degree of curvature and IIEF-5 was observed in combination therapy. Combination therapy may be the more effective than Potassium para-aminobenzoate monotherapy in medical treatment of Peyronie’s disease.

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

    PubMed

    Weng, Liming; Ziliak, Dana; Lacroix, Bonnie; Geeleher, Paul; Huang, R Stephanie

    2014-01-01

    It has long been observed that tamoxifen sensitivity varies among breast cancer patients. Further, ethnic differences of tamoxifen therapy between Caucasian and African American have also been reported. Since most studies have been focused on Caucasian people, we sought to comprehensively evaluate genetic variants related to tamoxifen therapy in African-derived samples. An integrative "omic" approach developed by our group was used to investigate relationships among endoxifen (an active metabolite of tamoxifen) sensitivity, SNP genotype, mRNA and microRNA expressions in 58 HapMap YRI lymphoblastoid cell lines. We identified 50 SNPs that associate with cellular sensitivity to endoxifen through their effects on 34 genes and 30 microRNA expression. Some of these findings are shared in both Caucasian and African samples, while others are unique in the African samples. Among gene/microRNA that were identified in both ethnic groups, the expression of TRAF1 is also correlated with tamoxifen sensitivity in a collection of 44 breast cancer cell lines. Further, knock-down TRAF1 and over-expression of hsa-let-7i confirmed the roles of hsa-let-7i and TRAF1 in increasing tamoxifen sensitivity in the ZR-75-1 breast cancer cell line. Our integrative omic analysis facilitated the discovery of pharmacogenomic biomarkers that potentially affect tamoxifen sensitivity. PMID:24699530

  20. Tamoxifen induction of angiogenic factor expression in endometrium

    PubMed Central

    Hague, S; Manek, S; Oehler, M K; MacKenzie, I Z; Bicknell, R; Rees, M C P

    2002-01-01

    Tamoxifen is the current therapy of choice for patients with oestrogen receptor positive breast cancer, and it is currently under evaluation as a prophylactic for women at high risk of developing the disease. However, tamoxifen is also known to induce proliferative changes in the endometrium increasing the risk of developing endometrial hyperplasia, polyps and carcinoma. Angiogenesis is an intimate part of this process. For this reason, we have examined the expression of several well characterized angiogenic factors, namely, acidic and basic fibroblast growth factor, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin in both normal and tamoxifen exposed pre- and postmenopausal endometrium. Vascular density and endothelial proliferation index were also quantified. We found increased expression of acidic and basic fibroblast growth factor and adrenomedullin after treatment with tamoxifen mainly in premenopausal tissue. Vascular density was significantly increased in pre- but not post-menopausal endometrium (P=0.0018) following tamoxifen treatment. These results support the notion that angiogenesis is integral to the response to tamoxifen exposure, and is a potential target with which to block these side effects of tamoxifen. British Journal of Cancer (2002) 86, 761–767. DOI: 10.1038/sj/bjc/6600157 www.bjcancer.com © 2002 Cancer Research UK PMID:11875740

  1. Estrogen receptor mutations in tamoxifen-resistant breast cancer.

    PubMed

    Karnik, P S; Kulkarni, S; Liu, X P; Budd, G T; Bukowski, R M

    1994-01-15

    Clinical resistance to antiestrogens like tamoxifen is a major problem in the treatment of hormone-dependent breast cancers. Since the estrogen receptor plays a central role in mediating the effects of estrogens and antiestrogens, we hypothesized that mutations in the estrogen receptor could be one mechanism by which breast tumors evolve from a hormone-dependent to a hormone-independent phenotype. The eight exons of the estrogen receptor complementary DNA from 20 tamoxifen-resistant and 20 tamoxifen-sensitive tumors were screened by Single Strand Conformation Polymorphism (SSCP), and the variant conformers were sequenced to identify the nucleotide changes. A 42-base pair replacement was found in exon 6 of a tamoxifen-resistant tumor. A single base pair deletion in exon 6 of a tamoxifen-resistant metastatic tumor but not in the primary tumor was detected in another case. If translated, both these mutations could generate truncated receptors with an intact DNA-binding domain and a defective hormone-binding domain that could constitutively activate transcription of previously estrogen-responsive genes. The remaining 18 of 20 tamoxifen-resistant tumors did not contain mutations in any of the 8 exons of the estrogen receptor complementary DNA. These results suggest that mutations in the estrogen receptor occur at a low frequency and do not account for most estrogen-independent, tamoxifen-resistant breast tumors. PMID:8275466

  2. Sorafenib and nilotinib resensitize tamoxifen resistant breast cancer cells to tamoxifen treatment via estrogen receptor α.

    PubMed

    Pedersen, Astrid M; Thrane, Susan; Lykkesfeldt, Anne E; Yde, Christina W

    2014-11-01

    Tamoxifen‑resistant breast cancer is a major clinical problem and new treatment strategies are highly warranted. In this study, the multitargeting kinase inhibitors sorafenib and nilotinib were investigated as potential new treatment options for tamoxifen‑resistant breast cancer. The two compounds inhibited cell growth, reduced expression of total estrogen receptor α (ER), Ser118-phosphorylated ER, FOXA1 and AIB1 and resensitized tamoxifen‑resistant cells to tamoxifen. The ER downmodulator fulvestrant exerted strong growth inhibition of tamoxifen‑resistant cells and addition of sorafenib and nilotinib could not further suppress growth, showing that sorafenib and nilotinib exerted growth inhibition via ER. In support of this, estradiol prevented sorafenib and nilotinib mediated growth inhibition. These results demonstrate that sorafenib and nilotinib act via ER and ER-associated proteins, indicating that these kinase inhibitors in combination with tamoxifen may be potential new treatments for tamoxifen‑resistant breast cancer. PMID:25175082

  3. Tamoxifen dose and serum concentrations of tamoxifen and six of its metabolites in routine clinical outpatient care.

    PubMed

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

    2014-02-01

    A sensitive and selective HPLC-MS/MS assay was used to analyze steady-state serum concentrations of tamoxifen, N-desmethyltamoxifen (E)-endoxifen, (Z)-endoxifen, N-desmethyl-4'-hydroxytamoxifen, 4-hydroxytamoxifen, and 4'-hydroxytamoxifen to support therapeutic drug monitoring (TDM) in patients treated with tamoxifen according to standard of care. When the (Z)-endoxifen serum concentration was below the predefined therapeutic threshold concentration of 5.9 ng/mL, the clinician was advised to increase the tamoxifen dose and to collect another serum sample. Paired serum samples from patients at one dose level at different time points during the tamoxifen treatment were used to assess the intra-patient variability. A total of 251 serum samples were analyzed, obtained from 205 patients. Of these patients, 197 used 20 mg tamoxifen per day and 8 patients used 10 mg/day. There was wide variability in tamoxifen and metabolite concentrations within the dosing groups. The threshold concentration for (Z)-endoxifen was reached in one patient (12 %) in the 10 mg group, in 153 patients (78 %) in the 20 mg group, and in 26 (96 %) of the patients who received a dose increase to 30 or 40 mg/day. Dose increase from 20 to 30 or 40 mg per day resulted in a significant increase in the mean serum concentrations of all analytes (p < 0.001). The mean intra-patient variability was between 10 and 20 % for all analytes. These results support the suitability of TDM for optimizing the tamoxifen treatment. It is shown that tamoxifen dose is related to (Z)-endoxifen exposure and increasing this dose leads to a higher serum concentration of tamoxifen and its metabolites. The low intra-patient variability suggests that only one serum sample is needed for TDM, making this a relatively noninvasive way to optimize the patient's treatment. PMID:24390246

  4. 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

  5. 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 ...

  6. Use of tamoxifen in the control of canine mammary neoplasia.

    PubMed

    Morris, J S; Dobson, J M; Bostock, D E

    1993-11-27

    Ninety-three bitches which had undergone mammary tumour surgery were entered into a clinical trial to examine the effects of ovariohysterectomy (spaying) at the time of mammary surgery and the use of the drug tamoxifen in preventing the recurrence of the tumour and/or the development of new mammary tumours. Twenty-three of the bitches which had been spayed were allocated tamoxifen but only 18 of them complied with the treatment and in nine of these the treatment was stopped owing to side effects (mostly oestrogenic). Too few animals were studied to draw conclusions about the possible preventative effects of tamoxifen on mammary neoplasia, but the high percentage of bitches affected by oestrogen-like side effects may reduce the compliance of owners and prevent tamoxifen being widely used in dogs. PMID:8116156

  7. 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

  8. Eslicarbazepine Acetate Monotherapy: A Review in Partial-Onset Seizures.

    PubMed

    Shirley, Matt; Dhillon, Sohita

    2016-04-01

    Eslicarbazepine acetate (Aptiom(®)) is a once-daily, orally administered antiepileptic drug (AED) approved previously in the EU, USA and several other countries for use as adjunctive therapy for the treatment of partial-onset seizures. Based on the findings of two randomized, dose-blinded, conversion-to-monotherapy phase III trials in patients with uncontrolled partial epilepsy, the US license for eslicarbazepine acetate has recently been expanded to include use as monotherapy for partial-onset seizures. The pivotal trials demonstrated that seizure control following conversion from other AEDs was superior for eslicarbazepine acetate monotherapy (1200 or 1600 mg once daily) compared with a pseudo-placebo historical control. Other efficacy outcomes appeared to support the benefit of treatment, with up to 10 % of patients remaining seizure free and up to 46 % of patients experiencing a ≥50 % reduction from baseline in standardized seizure frequency during the monotherapy periods of the trials. Eslicarbazepine acetate monotherapy was generally well tolerated, with most treatment-emergent adverse events being mild to moderate in severity. Its tolerability profile was generally consistent with the established profile of the drug based on its use as adjunctive therapy. Thus, once-daily eslicarbazepine acetate, either as monotherapy or adjunctive therapy, represents a useful option for the treatment of patients with partial-onset seizures. The recent licensing of the drug in the USA as monotherapy expands the range of treatment options for patients with partial-onset seizures and increases the opportunity to tailor therapy to the individual patient. PMID:27055527

  9. 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.

  10. 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

  11. Novel adjuvant systems.

    PubMed

    McCluskie, M J; Weeratna, R D

    2001-11-01

    Vaccination remains the single most valuable tool in the prevention of infectious disease. Nevertheless, there exists a need to improve the performance of existing vaccines such that fewer boosts are needed or to develop novel vaccines. For the development of effective vaccines for humans, a great need exists for safe and effective adjuvants. A number of novel adjuvants have been reported in recent years including: i) bacterial toxins such as cholera toxin, CT, and the Escherichia coli heat-labile enterotoxin, LT; ii) less toxic derivatives of CT and LT; iii) endogenous human immunomodulators, such as IL-2, IL-12, GM-CSF; iv) hormones; v) lipopeptides; vi) saponins, such as QS-21; vii) synthetic oligonucleotides containing CpG motifs (CpG ODN); viii) lipid 'A derivatives, such as monophosphoryl lipid A, MPL, and ix) muramyl dipeptide (MDP) derivatives. Herein, we will review recent findings using these novel adjuvant systems. PMID:12455400

  12. Leishmania is not prone to develop resistance to tamoxifen

    PubMed Central

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

    2015-01-01

    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. PMID:26150922

  13. Adjuvant Therapy for Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad A.

    2012-01-01

    Estimates from the U.S. Surveillance, Epidemiology, and End Results (SEER) registry suggest that melanoma incidence will reach 70,230 in 2011, of which 8,790 will die. The rising incidence and predilection for young individuals makes this tumor a leading source of lost productive years in the society. High-dose interferon-α2b is the only agent approved for adjuvant therapy of melanoma; the improvement in relapse-free survival has been observed across nearly all published studies and meta-analyses. However toxicity affects compliance and current research is focusing upon biomarkers that may allow selection of patients with greater likelihood of response, and exploring new agents either singly or in combination that may improve upon the benefit of IFN. In this article, we review the data for the adjuvant therapy of malignant melanoma - focusing on the results obtained with various regimens testing the several formulations of interferon-α2, and the adjuvant studies of vaccines and radiotherapy. Recent advances in the treatment of metastatic disease have established a role for CTLA-4 blockade and BRAF-inhibition, and raising hopes that these agents may have a role in the adjuvant setting. At present, several trials investigating combinations of novel agents with existing immunomodulators are underway. PMID:22453021

  14. 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

  15. 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. PMID:24575835

  16. The Role of MicroRNAs as Predictors of Response to Tamoxifen Treatment in Breast Cancer Patients.

    PubMed

    Egeland, Nina G; Lunde, Siri; Jonsdottir, Kristin; Lende, Tone H; Cronin-Fenton, Deirdre; Gilje, Bjørnar; Janssen, Emiel A M; Søiland, Håvard

    2015-01-01

    Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. However, resistance to endocrine therapy leads to breast cancer relapse. The recent extension of adjuvant tamoxifen treatment up to 10 years actualizes the need for identifying biological markers that may be used to monitor predictors of treatment response. MicroRNAs are promising biomarkers that may fill the gap between preclinical knowledge and clinical observations regarding endocrine resistance. MicroRNAs regulate gene expression by posttranscriptional repression or degradation of mRNA, most often leading to gene silencing. MicroRNAs have been identified directly in the primary tumor, but also in the circulation of breast cancer patients. The few available studies investigating microRNA in patients suggest that seven microRNAs (miR-10a, miR-26, miR-30c, miR-126a, miR-210, miR-342 and miR-519a) play a role in tamoxifen resistance. Ingenuity Pathway Analysis (IPA) reveals that these seven microRNAs interact more readily with estrogen receptor (ER)-independent pathways than ER-related signaling pathways. Some of these pathways are targetable (e.g., PIK3CA), suggesting that microRNAs as biomarkers of endocrine resistance may have clinical value. Validation of the role of these candidate microRNAs in large prospective studies is warranted. PMID:26473850

  17. The Role of MicroRNAs as Predictors of Response to Tamoxifen Treatment in Breast Cancer Patients

    PubMed Central

    Egeland, Nina G.; Lunde, Siri; Jonsdottir, Kristin; Lende, Tone H.; Cronin-Fenton, Deirdre; Gilje, Bjørnar; Janssen, Emiel A. M.; Søiland, Håvard

    2015-01-01

    Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. However, resistance to endocrine therapy leads to breast cancer relapse. The recent extension of adjuvant tamoxifen treatment up to 10 years actualizes the need for identifying biological markers that may be used to monitor predictors of treatment response. MicroRNAs are promising biomarkers that may fill the gap between preclinical knowledge and clinical observations regarding endocrine resistance. MicroRNAs regulate gene expression by posttranscriptional repression or degradation of mRNA, most often leading to gene silencing. MicroRNAs have been identified directly in the primary tumor, but also in the circulation of breast cancer patients. The few available studies investigating microRNA in patients suggest that seven microRNAs (miR-10a, miR-26, miR-30c, miR-126a, miR-210, miR-342 and miR-519a) play a role in tamoxifen resistance. Ingenuity Pathway Analysis (IPA) reveals that these seven microRNAs interact more readily with estrogen receptor (ER)-independent pathways than ER-related signaling pathways. Some of these pathways are targetable (e.g., PIK3CA), suggesting that microRNAs as biomarkers of endocrine resistance may have clinical value. Validation of the role of these candidate microRNAs in large prospective studies is warranted. PMID:26473850

  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. Ovarian tumors in postmenopausal breast cancer patients treated with tamoxifen.

    PubMed

    Cohen, I; Beyth, Y; Tepper, R; Shapira, J; Zalel, Y; Figer, A; Cordoba, M; Yigael, D; Altaras, M M

    1996-01-01

    From September 1, 1989, to November 30, 1994, 175 menopausal breast cancer patients treated with tamoxifen were followed at the authors' institutions. During this period. 16 (9.1%) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, for various indications. Of these, 10 (62.5%) had either uni- or bilateral ovarian tumors. The analysis of surgical findings showed an incidence of 5.7% (10/175) ovarian tumors among all the patients. In 2 (20%), the ovarian masses displayed enlargement over a relatively short period while on treatment. In 5 (50%) patients, the findings were bilateral. All tumors were detectable by ultrasonography, except four serous cystadenomas found in 3 women. The mean duration of tamoxifen treatment was 36.6 +/- 24.9 (range 9-86) months. The rate of 5.7% for ovarian tumors, in this selected group of patients, is four to five times higher than that reported for similar pathologic conditions detected by general screening with ultrasonographic scans among nonselected, asymptomatic, and untreated postmenopausal women. Two possibilities should be considered in the development of ovarian tumors coinciding with tamoxifen treatment; (1) women with breast malignancy are prone to develop benign or malignant ovarian tumors in relation to genetic factors, regardless of tamoxifen treatment; and (2) tamoxifen may stimulate enlargement of such tumors and may even cause them. PMID:8557228

  20. Tamoxifen stimulates in vivo growth of drug-resistant estrogen receptor-negative breast cancer.

    PubMed

    Maenpaa, J; Wiebe, V; Koester, S; Wurz, G; Emshoff, V; Seymour, R; Sipila, P; DeGregorio, M

    1993-01-01

    An estrogen receptor-negative, multidrug-resistant MDA-MB-A1 human breast cancer cell line was grown in culture with and without a noninhibitory concentration (0.5 microM) of tamoxifen for 122 days. Tamoxifen-treated and control cells were inoculated into opposite flanks of nine nude mice, where they produced measurable tumors in every case. Six of the animals were treated with tamoxifen at 500 micrograms/day for 22 days. Although no inhibitory nor stimulatory effect of tamoxifen was seen in vitro, tamoxifen had a clear tumor-growth-stimulating effect in mice. The most pronounced stimulatory effects were observed in the cells that had been cultured with tamoxifen. Within 3 weeks of the start of tamoxifen therapy, the cells grown in the presence of tamoxifen produced tumors with a mean size of 380 mm2, whereas the cells not pretreated with tamoxifen had tumors of 220 mm2. In contrast, in mice not receiving tamoxifen, the sizes of the tumors were 190 and 140 mm2, respectively. These preliminary results suggest that prolonged in vitro tamoxifen exposure induces cellular changes that result in tumors that are stimulated to grow faster in mice following tamoxifen treatment. PMID:8339392

  1. The First Electrochemical MIP Sensor for Tamoxifen

    PubMed Central

    Yarman, Aysu; Scheller, Frieder W.

    2014-01-01

    We present an electrochemical MIP sensor for tamoxifen (TAM)—a nonsteroidal anti-estrogen—which is based on the electropolymerisation of an O-phenylenediamine–resorcinol mixture directly on the electrode surface in the presence of the template molecule. Up to now only “bulk” MIPs for TAM have been described in literature, which are applied for separation in chromatography columns. Electro-polymerisation of the monomers in the presence of TAM generated a film which completely suppressed the reduction of ferricyanide. Removal of the template gave a markedly increased ferricyanide signal, which was again suppressed after rebinding as expected for filling of the cavities by target binding. The decrease of the ferricyanide peak of the MIP electrode depended linearly on the TAM concentration between 1 and 100 nM. The TAM-imprinted electrode showed a 2.3 times higher recognition of the template molecule itself as compared to its metabolite 4-hydroxytamoxifen and no cross-reactivity with the anticancer drug doxorubucin was found. Measurements at +1.1 V caused a fouling of the electrode surface, whilst pretreatment of TAM with peroxide in presence of HRP generated an oxidation product which was reducible at 0 mV, thus circumventing the polymer formation and electrochemical interferences. PMID:24776936

  2. [Monotherapy in treatment-naïve patients].

    PubMed

    Arranz Caso, José Alberto

    2008-12-01

    The development of antiretroviral therapy (ART) with current triple drug combinations has dramatically reduced morbidity and mortality in HIV-infected patients. However, there is a need for less toxic treatments without sacrificing efficacy, as well as for less expensive drugs to facilitate universal access to this therapy. The protease inhibitors (PI) administered with ritonavir have a favorable pharmacokinetic profile and high genetic barrier and consequently are ideal candidates for use in monotherapy, thus avoiding the toxicity and cost associated with nucleoside analogs, as well as preserving drugs for future options. The promising results of studies performed with lopinavir/ritonavir (LPV/r) in induction-maintenance regimens in patients without prior failure to PIs encourage research into the cost-effectiveness of LPV/r in monotherapy from the beginning of ART. The few studies performed in this context seem to indicate the following: a) LPV/r monotherapy achieves undetectable viral loads in a large proportion of treatment-naïve patients, b) future treatment options are not compromised in patients not achieving undetectable viral loads since the likelihood of resistance mutations is low and treatment intensification achieves suppression of viral replication, and c) strategies for early detection can probably be considered in patients who will not achieve complete suppression with LPV/r monotherapy. Nevertheless, before LPV/r monotherapy can be considered a first-line option, new studies with larger samples and longer follow-up are required. These studies should pay particular attention to viral replication in areas where PI show less penetration. PMID:19572437

  3. 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

  4. 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

  5. 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. PMID:26612479

  6. 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

  7. Adjuvant chemotherapy in early breast cancer.

    PubMed

    Ejlertsen, Bent

    2016-05-01

    these CMF regimens has not been compared within the context of a randomised trial. Shifting from the 77B's classic CMF regimen to the 82B four-weekly IV regimen or the 89B three-weekly IV regimen was associated with a 30% increased risk of a DFS event in a multivariate analysis of a population-based cohort study. Furthermore, the four-weekly regimen used in 82B was associated with a 40% increase in mortality. The strengths of the design include identical selection criteria, uniform and prospective registration of treatment, tumour and patient characteristics. Caution is still required due to the non-experimental design of the comparison. Another finding was a substantial difference in the risk of amenorrhoea; and while 15% of patients aged 40 or younger in 77B had regular menses throughout chemotherapy, the corresponding percentage was 37 in 82B and 47 in 89B. The DBCG in collaboration with a Swedish and a Dutch centre participating in the DBCG trial 89B compared CMF with ovarian ablation in premenopausal high-risk breast cancer patients with ER-positive tumours. No significant differences were found in DFS or OS in the preplanned analysis, suggesting that the benefits of CMF may, at least in part, be explained by ovarian suppression in premenopausal patients with ER-positive tumours. However, these results are not clinically useful by themselves as other chemotherapy regimens have been more efficacious, and knowledge is still lacking regarding the benefits from adding ovarian suppression to chemotherapy plus tamoxifen. The results from the DBCG 77B and 82C are in accordance with other large adjuvant trials and the EBCTCG meta-analyses. The benefits obtained with any individual anticancer drug are largely determined by the cancer (somatic) genome; and by being a molecular target of anthracyclines, TOP2A aberrations could obviously be associated with cancer drug benefits. In the DBCG 89D, a significant heterogeneity was observed between a beneficial effect on DFS and OS

  8. 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

  9. Comparative uterotrophic effects of endoxifen and tamoxifen in ovariectomized Sprague-Dawley rats.

    PubMed

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

    2014-12-01

    Endoxifen (4-hydroxy-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 3 days. Estradiol was the positive control. Endoxifen and tamoxifen plasma levels exceeded those previously observed clinically. Uterine weight was 3-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

  10. 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

  11. Adjuvant Therapy Trials.

    PubMed

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

    2016-01-01

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

  12. 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

  13. 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.

  14. 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...

  15. 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

  16. Adjuvant Therapy: Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad; Kirkwood, John M.

    2011-01-01

    With an incidence that is increasing at 2–5% per year, cutaneous melanoma is an international scourge that disproportionately targets young individuals. Despite much research, the treatment of advanced disease is still quite challenging. Immunotherapy with high-dose interferon-α2b or interleukin-2 benefits a select group of patients in the adjuvant and metastatic settings, respectively, with significant attendant toxicity. Advances in the biology of malignant melanoma and the role of immunomodulatory therapy have produced advances that have stunned the field. In this paper, we review the data for the use of interferon-α2b in various dosing ranges, vaccine therapy, and the role of radiotherapy in the adjuvant setting for malignant melanoma. Recent trials in the metastatic setting using anticytoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody therapy and BRAF inhibitor therapy have demonstrated clear benefit with prolongation of survival. Trials investigating combinations of these novel agents with existing immunomodulators are at present underway. PMID:22220281

  17. 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

  18. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine.

    PubMed

    Podda, A

    2001-03-21

    Elderly people and subjects with underlying chronic diseases are at increased risk for influenza and related complications. Conventional influenza vaccines provide only limited protection in the elderly population. In order to enhance the immune response to influenza vaccines, several adjuvants have been evaluated. Among these, an oil in water adjuvant emulsion containing squalene, MF59, has been combined with subunit influenza antigens and tested in clinical trials in comparison with non-adjuvanted conventional vaccines. Data from a clinical database of over 10000 elderly subjects immunised with this adjuvanted vaccine (Fluad, Chiron Vaccines, Siena, Italy) demonstrate that, although common postimmunisation reactions are more frequent in recipients of the adjuvanted vaccine, this vaccine is well tolerated, also after re-immunisation in subsequent influenza seasons. Immunogenicity analyses demonstrate a consistently higher immune response with statistically significant increases of postimmunisation geometric mean titres, and of seroconversion and seroprotection rates compared to non-adjuvanted subunit and split influenza vaccines, particularly for the A/H3N2 and the B strains. The higher immunogenicity profile of the MF59-adjuvanted vaccine is maintained also after subsequent immunisations. An even higher adjuvant effect was shown in subjects with low pre-immunisation titre and in those affected by chronic underlying diseases. In conclusion, the addition of MF59 to subunit influenza vaccines enhances significantly the immune response in elderly subjects without causing clinically important changes in the safety profile of the influenza vaccine. PMID:11257408

  19. 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

  20. Receipt of Glucocorticoid Monotherapy Among Medicare Beneficiaries With Rheumatoid Arthritis

    PubMed Central

    YAZDANY, JINOOS; TONNER, CHRIS; SCHMAJUK, GABRIELA; LIN, GRACE A.; TRIVEDI, AMAL N.

    2015-01-01

    Objective Using disease-modifying antirheumatic drugs (DMARDs) improves outcomes in rheumatoid arthritis (RA) and is a nationally endorsed quality measure. We investigated the prevalence and predictors of receiving glucocorticoids alone for the treatment of RA in a nationwide sample of Medicare beneficiaries. Methods Among individuals ages ≥65 years with RA enrolled in the Part D prescription drug benefit in 2009, we compared those with ≥1 DMARD claim to those receiving glucocorticoid monotherapy, defined as no DMARD claim and an annual glucocorticoid supply of ≥180 days or an annual dose of ≥900 mg of prednisone or equivalent. We fit multivariable models to determine the sociodemographic and clinical factors associated with glucocorticoid monotherapy. Results Of 8,125 beneficiaries treated for RA, 10.2% (n = 825) received glucocorticoids alone. Beneficiaries with low incomes were more likely to receive glucocorticoids alone (12.3%; 95% confidence interval [95% CI] 10.9–13.8% versus 9.4%; 95% CI 8.6–10.1%), as were those living in certain US regions. More physician office visits and hospitalizations were associated with glucocorticoid monotherapy. Individuals who had no contact with a rheumatologist were significantly more likely to receive glucocorticoids alone (17.5%; 95% CI 16.0–19.0% versus 8.5%; 95% CI 7.4–9.5% for those with no rheumatology visits versus 1–4 visits). Conclusion Approximately 1 in 10 Medicare beneficiaries treated for RA received glucocorticoids without DMARDs in 2009. Compared to DMARD users, glucocorticoid users were older, had lower incomes, were more likely to live in certain US regions, and were less likely to have seen a rheumatologist, suggesting persistent gaps in quality of care despite expanded drug coverage under Part D. PMID:25244314

  1. Extensive Darier Disease Successfully Treated with Doxycycline Monotherapy

    PubMed Central

    Sfecci, Alicia; Orion, Camille; Darrieux, Laure; Tisseau, Laurent; Safa, Gilles

    2015-01-01

    Darier disease (DD) is a rare dominantly inherited genodermatosis characterized by loss of intercellular adhesion (acantholysis) and abnormal keratinization. DD is often difficult to manage. Numerous treatments have reportedly been used for the treatment of DD, with limited success. Systemic retinoids are considered the drug of choice for treating DD. However, their use is limited by potential deleterious side effects. Considering the recently reported efficacy of doxycycline for Hailey-Hailey disease, an inherited acantholytic skin disorder pathogenetically similar to DD, we report the case of a patient with extensive DD who showed a dramatic response to oral doxycycline monotherapy. PMID:26594170

  2. Extensive Darier Disease Successfully Treated with Doxycycline Monotherapy.

    PubMed

    Sfecci, Alicia; Orion, Camille; Darrieux, Laure; Tisseau, Laurent; Safa, Gilles

    2015-01-01

    Darier disease (DD) is a rare dominantly inherited genodermatosis characterized by loss of intercellular adhesion (acantholysis) and abnormal keratinization. DD is often difficult to manage. Numerous treatments have reportedly been used for the treatment of DD, with limited success. Systemic retinoids are considered the drug of choice for treating DD. However, their use is limited by potential deleterious side effects. Considering the recently reported efficacy of doxycycline for Hailey-Hailey disease, an inherited acantholytic skin disorder pathogenetically similar to DD, we report the case of a patient with extensive DD who showed a dramatic response to oral doxycycline monotherapy. PMID:26594170

  3. Effective treatment of bipolar depression: monotherapy and combination strategies.

    PubMed

    Manning, J Sloan

    2015-11-01

    Managing patients with bipolar disorder remains a challenge due to its chronic nature. In addition, bipolar depression remains understudied even though patients spend more time in depressive episodes than in manic ones. Effective treatment requires an accurate and timely diagnosis, psychoeducation, psychotherapy, pharmacotherapy, and implementation of elements of the chronic care model. Pharmacologic strategies for treating bipolar depression differ from those for bipolar mania as well as those for unipolar depression and require knowledge of the efficacy and safety of agents including mood stabilizers, atypical antipsychotics, and antidepressants both as monotherapy and in combination. PMID:26646048

  4. Association of tamoxifen with meningioma: a population-based study in Sweden

    PubMed Central

    Sundquist, Jan; Sundquist, Kristina

    2016-01-01

    Previous studies suggest that hormone therapy may play an important role in the development of meningioma. However, it is unclear whether medication with tamoxifen can prevent meningioma. Our study cohort included all women who were diagnosed with breast cancer between 1961 and 2010, and a total of 227 535 women were identified with breast cancer with a median age at diagnosis of 63 years. Women diagnosed with breast cancer after 1987 were defined as tamoxifen exposed; those diagnosed with breast cancer before or during 1987 were defined as not exposed to tamoxifen. Standardized incidence ratios (SIRs) were used to calculate the risk of subsequent meningioma. Of these women, 223 developed meningioma. For women without tamoxifen exposure, the risk of meningioma was significantly increased, with an SIR of 1.54 (95% confidence interval 1.30–1.81); the risk was not increased in those with tamoxifen exposure (SIR=1.06, 95% confidence interval 0.84–1.32). The increased risk of meningioma in women without tamoxifen exposure persisted during 10 years of follow-up. In this historical cohort study, we found that women diagnosed with breast cancer but not treated with tamoxifen had an increased incidence of meningioma, whereas the incidence was close to that of the general population in patients treated with tamoxifen. This suggests that tamoxifen may prevent the development of meningioma. PMID:25642792

  5. Ovarian cyst formation in two pre-menopausal patients treated with tamoxifen for breast cancer.

    PubMed

    Shulman, A; Cohen, I; Altaras, M M; Maymon, R; Ben-Nun, I; Tepper, R; Beyth, Y

    1994-08-01

    Pre-menopausal tamoxifen treatment causes hyperoestrogen production and ovarian cyst formation. Two pre-menopausal breast cancer patients who were treated with tamoxifen developed both permanent supraphysiological oestrogen concentration and ovarian cysts. Serum oestrogen decreased to post-menopausal concentrations and ovarian cysts completely resolved during and following simultaneous treatment with tamoxifen and gonadotrophin-releasing hormone agonist (GnRHa). In pre-menopausal breast cancer patients, GnRHa may prevent possible side-effects of tamoxifen, such as ovarian cysts and supraphysiological oestrogen production. PMID:7989499

  6. 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.

  7. Roles of the ER-α36-EGFR/HER2 positive regulatory loops in tamoxifen resistance.

    PubMed

    Yin, Li; Wang, Zhao-Yi

    2016-07-01

    Tamoxifen provided a successful treatment for ER-positive breast cancer for the past four decades. However, most breast tumors are eventually resistant to tamoxifen therapy. Extensive researches were conducted to understand the molecular mechanisms involved in tamoxifen resistance, and have revealed that multiple signaling molecules and pathways such as EGFR and HER2 are involved in tamoxifen resistance. Currently, the mechanisms by which tamoxifen sensitive breast cancer cells acquire these signaling pathways and develop tamoxifen resistance have not been elucidated. The identification of ER-α36, a variant of ER-α, that is able to mediate agonist activity of tamoxifen provided great insights into the underlying mechanisms of tamoxifen resistance. In this review, we will discuss the biological function and the possible underlying mechanisms of ER-α36 in tamoxifen resistance and specifically illustrate a novel cross-talk mechanism; positive regulatory loops between the ER-α36 and EGFR/HER2 in tamoxifen resistance. The function and the underlying mechanisms of ER-α36 in tamoxifen resistance of the breast cancer stem/progenitor cells will also be discussed. Finally, we will postulate a novel approach to restore tamoxifen sensitivity in tamoxifen resistant breast cancer cells. PMID:26884313

  8. 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.

  9. Innate immunity and adjuvants.

    PubMed

    Akira, Shizuo

    2011-10-12

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

  10. 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

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

    PubMed Central

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

    2015-01-01

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

  12. 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

  13. 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

  14. 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

  15. Long-term outcome of adjuvant chemotherapy cyclophosphamide, mitoxantrone, and fluorouracil in women with breast cancer.

    PubMed

    Kumpulainen, Eero J; Hirvikoski, Pasi P; Johansson, Risto T

    2008-01-01

    The aim of the study is to report the long-term outcome and secondary tumours of early breast cancer patients of adjuvant CNF (cyclophosphamide, mitoxantrone, and 5-fluorouracil) chemotherapy. One hundred and ninety four patients, 185 primary early breast cancer and nine locoregionally recurrent breast cancer patients, were entered onto the trial between May 1986 and November 1993. The therapies included surgery, radiation therapy, adjuvant CNF chemotherapy, and tamoxifen according to hormonal status. Some of patients were treated twice with CMF (methotrexate). The median follow-up time was 12.9 years. Eighty nine (48%) primary breast cancers relapsed, and six locoregional breast cancers relapsed. After 5-10 years the relapse incidence decreased notably. Eighty three patients died of breast cancer, and nine of other causes. Two cases of leukemia, six cases of skin cancer, two cases of Hodgkin's disease, two cases of meningioma, and two cases of endometrial cancer were observed. This article confirms the feasibility of adjuvant CNF for early breast cancer patients. Questions of possible causability of secondary cancer have yet to be explored. PMID:18097780

  16. Further characterization of a ¹³C-dextromethorphan breath test for CYP2D6 phenotyping in breast cancer patients on tamoxifen therapy.

    PubMed

    Opdam, F L; Modak, A S; Gelderblom, H; Guchelaar, H J

    2015-06-01

    In a previous study, we found that the CYP2D6 phenotype determined by (13)C-dextromethorphan breath test (DM-BT) might be used to predict tamoxifen treatment outcome in breast cancer patients in the adjuvant setting. However, large variation in the delta-over-baseline (DOB) values was observed in the extensive metabolizer predicted phenotype group based on single point measures. In the present work we aimed to analyze the variability of phenotype results and determine reproducibility to further characterize the clinical utility of DM-BT by introducing multiple breath sampling instead of single breath sampling and by administration of a fixed dose of (13)C-DM. PMID:25891764

  17. 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

  18. 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...

  19. Tamoxifen favoured the rat sensorial cortex regeneration after a penetrating brain injury.

    PubMed

    Franco Rodríguez, N E; Dueñas Jiménez, J M; De la Torre Valdovinos, B; López Ruiz, J R; Hernández Hernández, L; Dueñas Jiménez, S H

    2013-09-01

    A penetrating brain injury produces a glial scar formed by astrocytes, oligodendrocytes, microglia and NG2 cells. Glial scar is a barrier preventing the extent of damage but it has deleterious effects in the regeneration of the axons. Estradiol and tamoxifen reduce gliosis and have neuroprotective effects in the hippocampus and the spinal cord. We evaluated the proliferation of glia and the electrocorticogram in the sensorial cortex in a brain injury model. At seven days post-injury, estradiol, tamoxifen and estradiol plus tamoxifen reduced the number of resident and proliferative NG2 and reactive astrocyte vimentin+ cells. Estradiol and tamoxifen effects on NG2 cells could be produced by the classical oestrogen receptors found in these cells. The glial scar was also reduced by tamoxifen. At thirty days post-injury, the amount of resident and proliferative astrocytes increased significantly, except in the estradiol plus tamoxifen group, whilst the oligodendrocytes proliferation in the glial scar was reduced in treated animals. Tamoxifen promotes the survival of FOX-3+ neurons in the injured area and a recovery in the amplitude of electrocorticogram waves. At thirty days, estradiol did not favour the survival of neurons but produced a greater number of reactive astrocytes. In contrast, the number of oligodendrocytes was reduced. Tamoxifen could favour brain repair promoting neuron survival and adjusting glial cell number. It seems to recover adequate neural communication. PMID:23886572

  20. 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

  1. High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy

    PubMed Central

    Gonzalez-Malerva, Laura; Park, Jaehong; Zou, Lihua; Hu, Yanhui; Moradpour, Zahra; Pearlberg, Joseph; Sawyer, Jacqueline; Stevens, Hallam; Harlow, Ed; LaBaer, Joshua

    2011-01-01

    Resistance to tamoxifen in breast cancer patients is a serious therapeutic problem and major efforts are underway to understand underlying mechanisms. Resistance can be either intrinsic or acquired. We derived a series of subcloned MCF7 cell lines that were either highly sensitive or naturally resistant to tamoxifen and studied the factors that lead to drug resistance. Gene-expression studies revealed a signature of 67 genes that differentially respond to tamoxifen in sensitive vs. resistant subclones, which also predicts disease-free survival in tamoxifen-treated patients. High-throughput cell-based screens, in which >500 human kinases were independently ectopically expressed, identified 31 kinases that conferred drug resistance on sensitive cells. One of these, HSPB8, was also in the expression signature and, by itself, predicted poor clinical outcome in one cohort of patients. Further studies revealed that HSPB8 protected MCF7 cells from tamoxifen and blocked autophagy. Moreover, silencing HSBP8 induced autophagy and caused cell death. Tamoxifen itself induced autophagy in sensitive cells but not in resistant ones, and tamoxifen-resistant cells were sensitive to the induction of autophagy by other drugs. These results may point to an important role for autophagy in the sensitivity to tamoxifen. PMID:21233418

  2. Survival in renal cell carcinoma-a randomized evaluation of tamoxifen vs interleukin 2, alpha-interferon (leucocyte) and tamoxifen.

    PubMed Central

    Henriksson, R.; Nilsson, S.; Colleen, S.; Wersäll, P.; Helsing, M.; Zimmerman, R.; Engman, K.

    1998-01-01

    Metastatic renal cell carcinoma (RCC) has a poor prognosis. Conventional treatment strategies, including chemotherapy and hormonal therapy, have limited value. Although encouraging results have been achieved in terms of objective response using immunological manipulations, no conclusive studies yet exist with a controlled comparative evaluation of survival. Therefore, the present study was undertaken, which compared one of the present (and presumed best) treatments, interleukin 2/interferon-alpha (IL-2/IFN-alpha) and tamoxifen, with a control arm of tamoxifen only. Tamoxifen has been shown to potentiate in vivo anti-tumour activity of IL-2, and because of its non-toxic behaviour it was included in both groups. The study was open, randomized and included seven institutions in Sweden. The patients were stratified according to the different centres involved. An interim analysis was planned when a minimum of 100 patients were evaluable. The 128 patients finally included had a histologically documented metastatic RCC, with a life expectancy of more than 3 months, a performance status WHO 0-2 and no prior chemo- or immunotherapy. Informed consent was obtained from each patient. The patients randomized to the control arm (n = 63) received only tamoxifen 40 mg p.o. daily for at least 1 year or until progression. The patients (n = 65) randomized to biotherapy received subcutaneous recombinant IL-2, leucocyte IFN-alpha in a treatment cycle of 42 days, as well as tamoxifen p.o. In the absence of undue toxicity or disease progression, these patients received one additional treatment cycle of 42 days followed by maintenance treatment, consisting of 5 days therapy every 4 weeks, for 1 year, or until proven progression. Only two patients in the tamoxifen-only group received immunotherapy when the disease progressed, but without any beneficial effect. All patients received appropriate local treatment when indicated. The interim analysis demonstrated no survival advantage for

  3. Classification of Laser Vaccine Adjuvants

    PubMed Central

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

    2016-01-01

    An immunologic adjuvant, which enhances the magnitude and quality of immune responses to vaccine antigens, has become an essential part of modern vaccine practice. Chemicals and biologicals have been typically used for this purpose, but there are an increasing number of studies that are being conducted on the vaccine adjuvant effect of laser light on the skin. Currently, four different types or classes of laser devices have been shown to systemically enhance immune responses to intradermal vaccination: ultra-short pulsed lasers, non-pulsed lasers, non-ablative fractional lasers and ablative fractional lasers. Aside from involving the application of laser light to the skin in a manner that minimizes discomfort and damage, each type of laser vaccine adjuvant involves emission parameters, modes of action and immunologic adjuvant effects that are quite distinct from each other. This review provides a summary of the four major classes of “laser vaccine adjuvant” and clarifies and resolves their characteristics as immunologic adjuvants. These aspects of each adjuvant’s properties will ultimately help define which laser would be most efficacious in delivering a specific clinical benefit with a specific vaccine. PMID:27104047

  4. 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 Central

    Du, Xianglin L.

    2016-01-01

    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. PMID:26786154

  5. 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

  6. [Thrombophlebitis in an Elderly Japanese Woman Treated with Tamoxifen for Breast Cancer].

    PubMed

    Takayanagi, Hiroyuki; Hayami, Ryosuke; Tsuneizumi, Michiko; Nakagami, Kazuhiko

    2015-10-01

    In this study, we report the rare case of an elderly woman who developed thrombophlebitis after being treated with tamoxifen for breast cancer. She visited our department with a lump in her left breast. She underwent core needle biopsy, and she was diagnosed with breast cancer (invasive ductal carcinoma, ER- and PgR-positive, HER2-negative). We chose hormonal therapy because surgical treatment was deemed too invasive considering her general status. She was administered tamoxifen (20 mg/day) instead of an aromatase inhibitor in consideration of her osteoporosis. Six months after initiating tamoxifen therapy, she exhibited swelling in her left leg. Computed tomography and ultrasound revealed thrombophlebitis in her left femoral vein. She stopped taking tamoxifen and started warfarin potassium as thrombolytic therapy, after which thrombophlebitis was relieved. Advanced age may be a risk factor for thrombophlebitis associated with tamoxifen treatment; therefore, precautions should be taken accordingly. PMID:26489549

  7. 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

  8. 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

  9. [A case of nephrotic syndrome achieving remission with cyclosporine monotherapy].

    PubMed

    Nagatoya, Katsuyuki

    2010-01-01

    The case was a female in her early 80's. Due to abdominal bloating and lower limb edema, she visited a nearby doctor, was diagnosed to have nephrotic syndrome, and then was referred to our department. Upon initial consultation, TP of 4.1 g/dl, Alb of 1.7 g/dl, UN of 73 mg/dl, and Cr of 1.43 mg/dl, along with pleural effusion were observed by chest X-ray. A renal biopsy was not performed because permission could not be obtained. Despite the fact that management of the edema was performed using diuretic agents and albumin preparations, a reduced renal function and deterioration of the fluid retention were gradually observed. She originally displayed lower back pain and digestive symptoms and, therefore, cyclosporine monotherapy was initiated in order to address concerns of side effects such as osteoporosis and peptic ulcer due to adrenocortical steroid drugs (hereinafter abbreviated as steroid). Subsequently, hemodialysis was temporarily required but reduced urine protein and an improved renal function were gradually observed and she eventually achieved a complete remission. The possibility of a spontaneous remission of membranous nephropathy, etc. was considered, but a relapse occurred when the amount of cyclosporine was reduced. Thereafter, a complete remission was obtained with an increased dosage. As a result, the effectiveness of cyclosporine was thus confirmed. In treating nephrotic syndrome, steroid therapy is commonly performed and it is common for cyclosporine to be limited to steroid-resistant cases and/or steroid-dependent cases. However, it is believed that monotherapy could also be an option in cases in which the use of steroids is difficult, such as in cases of elderly patients. PMID:21116092

  10. Adjuvant treatment for pancreatic cancer.

    PubMed

    Daoud, Vladimir; Saif, Muhammad Wasif; Goodman, Martin

    2014-07-01

    Pancreatic cancer is the fourth leading cause of cancer deaths in both men and women. Surgical resection has been shown to be the only curable treatment available. Unfortunately only 20% of all patients diagnosed with pancreatic cancer are surgical candidates due to the aggressive biology of this disease. There is no clear consensus on what type of adjuvant therapy should be used for patients with pancreatic cancer. Chemoradiation is the favored treatment modality by many in the United States while gemcitabine based chemotherapy is favored in Europe. Both of these approaches have been shown by large prospective, randomized trials to improve disease free intervals and in some studies overall survival. The survival of these patients, even status post resection and adjuvant therapy, remains poor and therefore the need for alternative adjuvant therapies is needed. We will therefore discuss Abstracts #4124, #TPS4162, #4120 and #E15191 in this paper which are relevant to the issues described above. PMID:25076340

  11. Chemokines as Cancer Vaccine Adjuvants

    PubMed Central

    Bobanga, Iuliana D.; Petrosiute, Agne; Huang, Alex Y.

    2013-01-01

    We are witnessing a new era of immune-mediated cancer therapies and vaccine development. As the field of cancer vaccines advances into clinical trials, overcoming low immunogenicity is a limiting step in achieving full success of this therapeutic approach. Recent discoveries in the many biological roles of chemokines in tumor immunology allow their exploitation in enhancing recruitment of antigen presenting cells (APCs) and effector cells to appropriate anatomical sites. This knowledge, combined with advances in gene therapy and virology, allows researchers to employ chemokines as potential vaccine adjuvants. This review will focus on recent murine and human studies that use chemokines as therapeutic anti-cancer vaccine adjuvants. PMID:24967094

  12. MiR-27b is epigenetically downregulated in tamoxifen resistant breast cancer cells due to promoter methylation and regulates tamoxifen sensitivity by targeting HMGB3.

    PubMed

    Li, Xiunan; Wu, Yumei; Liu, Aihui; Tang, Xin

    2016-09-01

    MiR-27b downregulation is significantly associated with tamoxifen resistance in breast cancer cells. However, how it is downregulated in tamoxifen resistant (TamR) breast cancer cells and its downstream regulation were not clear. By performing MSP assay and QRT-PCR analysis with the use of 5-AZA-dC, a DNA methyltransferase inhibitor, we observed that TamR MCF-7 cells had significantly higher levels of methylation in the miR-27b promoter region than tamoxifen sensitive MCF-7 (TamS) cells and demethylation restored miR-27b expression. Re-expression of miR-27b sensitized TamR MCF-7 cells to tamoxifen, inhibited invasion and reversed epithelial-mesenchymal transition (EMT)-like properties. By using bioinformatics analysis and following dual luciferase and western blot analysis, this study confirmed a direct regulation of miR-27b on HMGB3 expression by binding to the 3'UTR. In addition, this study also found that silencing of HMGB3 indeed partially phenocopied the effects of miR-27b in reducing tamoxifen resistance and cell invasion and in reversing EMT-like properties. Therefore, we infer that HMGB3 is a functional target of miR-27b in modulation of tamoxifen resistance and EMT. PMID:27363334

  13. 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

  14. 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. PMID:26276354

  15. 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.

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

    PubMed Central

    2011-01-01

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

  17. Tamoxifen induces pleiotrophic changes in mammary stroma resulting in extracellular matrix that suppresses transformed phenotypes

    PubMed Central

    Hattar, Rhonda; Maller, Ori; McDaniel, Shauntae; Hansen, Kirk C; Hedman, Karla J; Lyons, Traci R; Lucia, Scott; Wilson, R Storey; Schedin, Pepper

    2009-01-01

    Introduction The functional unit of the mammary gland has been defined as the epithelial cell plus its microenvironment, a hypothesis that predicts changes in epithelial cell function will be accompanied by concurrent changes in mammary stroma. To test this hypothesis, the question was addressed of whether mammary stroma is functionally altered by the anti-oestrogen drug tamoxifen. Methods Forty female rats at 70 days of age were randomised to two groups of 20 and treated with 1.0 mg/kg tamoxifen or vehicle subcutaneously daily for 30 days, followed by a three-day wash out period. Mammary tissue was harvested and effects of tamoxifen on mammary epithelium and stroma determined. Results As expected, tamoxifen suppressed mammary alveolar development and mammary epithelial cell proliferation. Primary mammary fibroblasts isolated from tamoxifen-treated rats displayed a three-fold decrease in motility and incorporated less fibronectin in their substratum in comparison to control fibroblasts; attributes indicative of fibroblast quiescence. Immunohistochemistry analysis of CD68, a macrophage lysosomal marker, demonstrated a reduction in macrophage infiltration in mammary glands of tamoxifen-treated rats. Proteomic analyses by mass spectrometry identified several extracellular matrix (ECM) proteins with expression levels with tamoxifen treatment that were validated by Western blot. Mammary tissue from tamoxifen-treated rats had decreased fibronectin and increased collagen 1 levels. Further, ECM proteolysis was reduced in tamoxifen-treated rats as detected by reductions in fibronectin, laminin 1, laminin 5 and collagen 1 cleavage fragments. Consistent with suppression in ECM proteolysis with tamoxifen treatment, matrix metalloproteinase-2 levels and activity were decreased. Biochemically extracted mammary ECM from tamoxifen-treated rats suppressed in vitro macrophage motility, which was rescued by the addition of proteolysed collagen or fibronectin. Mammary ECM from

  18. New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

    PubMed Central

    Jordan, V. Craig

    2009-01-01

    The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyl tamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen. PMID:17765940

  19. Drift reduction with drift control adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  20. Spray drift mitigation with spray mix adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  1. Drift reduction with drift control adjuvants

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  2. 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...

  3. 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

  4. 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.

  5. 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

  6. 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

  7. Tamoxifen encapsulation within polyethylene glycol-coated nanospheres. A new antiestrogen formulation.

    PubMed

    Brigger, I; Chaminade, P; Marsaud, V; Appel, M; Besnard, M; Gurny, R; Renoir, M; Couvreur, P

    2001-02-19

    When dealing with solid tumors in vivo, pegylated long-circulating carrier systems show, after intravenous administration, an attractive extravasation profile with an enhanced localization in the tumoral interstitium. These systems could be of help for the delivery of cancer fighting drugs, such as Tamoxifen, a well known antiestrogen used in breast cancer therapy that possesses an extended biodistribution in vivo. This work aimed at encapsulating Tamoxifen in long-circulating poly(MePEGcyanoacrylate-co-hexadecylcyanoacrylate) 1:4 nanospheres. Tamoxifen-loaded poly(MePEGcyanoacrylate-co-hexadecylcyanoacrylate) nanospheres were successfully synthesized and characterized in terms of hydrophilicity/hydrophobicity by a model made up from near infrared spectra using principal component analysis. Zeta potential, drug loading, encapsulation efficiency, as well as biological effect, in vitro release and nanospheres integrity were also investigated. Even though near infrared spectroscopy could not detect Tamoxifen, it revealed that Pluronic F68 was associated with the pegylated nanospheres. HPLC measurements demonstrated that Tamoxifen was encapsulated in the pegylated nanospheres following a partition equilibrium between the polymeric and the aqueous phases. The Tamoxifen encapsulated in the nanospheres still showed a transcription inhibitory activity in ex vivo experiments. However, zeta potential and in vitro release suggested that Tamoxifen was essentially localized at the nanoparticles surface, resulting in an important and immediate drug release. PMID:11282234

  8. 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

  9. Tamoxifen-associated skin reactions in breast cancer patients: from case report to literature review.

    PubMed

    Andrew, Peter; Valiani, Sabira; MacIsaac, Jennifer; Mithoowani, Hamid; Verma, Shailendra

    2014-11-01

    The purpose of this study was to firstly present the maiden case of tamoxifen-induced acute cutaneous lupus erythematosus (ACLE), and secondly, to broaden the discussion into a systematic review of the various tamoxifen-related skin changes documented in patients with breast cancer. We searched PubMed, Cochrane, Embase, CancerLit, Scopus, Web of Science, and Google Scholar databases using keywords to identify reported cases of tamoxifen-related cutaneous adverse events. Outcomes captured included type of cutaneous reaction, time to adverse event, pathologic mechanism, and possible treatment. From 17 clinical studies identified, over ten distinct types of adverse reactions of the skin were itemized. The character of these cutaneous events ranged from the relatively common hot flashes to the rare, but potentially life-threatening, Steven Johnson syndrome. Overall, tamoxifen is generally a well-tolerated hormone therapy with decades of supporting safety data. Based on current medical literature, we present the first case of tamoxifen-induced ACLE. Our clinical experience of managing this case revealed that despite its broad use and the frequency of associated skin reactions, there is a lack of concise information detailing the cutaneous adverse events associated with tamoxifen. The absence of summarized information concerning tamoxifen-related skin changes prompted us to perform a review herein. PMID:25292419

  10. Coprescription of Tamoxifen and Medications That Inhibit CYP2D6

    PubMed Central

    Sideras, Kostandinos; Ingle, James N.; Ames, Matthew M.; Loprinzi, Charles L.; Mrazek, David P.; Black, John L.; Weinshilboum, Richard M.; Hawse, John R.; Spelsberg, Thomas C.; Goetz, Matthew P.

    2010-01-01

    Evidence has emerged that the clinical benefit of tamoxifen is related to the functional status of the hepatic metabolizing enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6 is the key enzyme responsible for the generation of the potent tamoxifen metabolite, endoxifen. Multiple studies have examined the relationship of CYP2D6 status to breast cancer outcomes in tamoxifen-treated women; the majority of studies demonstrated that women with impaired CYP2D6 metabolism have lower endoxifen concentrations and a greater risk of breast cancer recurrence. As a result, practitioners must be aware that some of the most commonly prescribed medications coadministered with tamoxifen interfere with CYP2D6 function, thereby reducing endoxifen concentrations and potentially increasing the risk of breast cancer recurrence. After reviewing the published data regarding tamoxifen metabolism and the evidence relating CYP2D6 status to breast cancer outcomes in tamoxifen-treated patients, we are providing a guide for the use of medications that inhibit CYP2D6 in patients administered tamoxifen. PMID:20439629

  11. Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients.

    PubMed

    Binkhorst, Lisette; Kloth, Jacqueline S L; de Wit, Annelieke S; de Bruijn, Peter; Lam, Mei H; Chaves, Ines; Burger, Herman; van Alphen, Robbert J; Hamberg, Paul; van Schaik, Ron H N; Jager, Agnes; Koch, Birgit C P; Wiemer, Erik A C; van Gelder, Teun; van der Horst, Gijsbertus T J; Mathijssen, Ron H J

    2015-07-01

    The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen C(max )and area under the curve (AUC)0-8 h were 20 % higher (P < 0.001), and tamoxifen t(max) was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0-24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen. PMID:26050156

  12. 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

  13. Serum concentrations of tamoxifen and its metabolites increase with age during steady-state treatment.

    PubMed

    Lien, Ernst A; Søiland, Håvard; Lundgren, Steinar; Aas, Turid; Steen, Vidar M; Mellgren, Gunnar; Gjerde, Jennifer

    2013-09-01

    It has been suggested that the concentrations of tamoxifen and its demethylated metabolites increase with age. We measured the serum concentrations of the active tamoxifen metabolites, 4OHtamoxifen (4OHtam), 4-hydroxy-N-desmethyltamoxifen (4OHNDtam, Endoxifen), tamoxifen and its demethylated metabolites. Their relations to age were examined. One hundred fifty-one estrogen receptor and/or progesterone receptor positive breast cancer patients were included. Their median (range) age was 57 (32-85) years. Due to the long half-life of tamoxifen, only patients treated with tamoxifen for at least 80 days were included in the study in order to insure that the patients had reached steady-state drug levels. Tamoxifen and its metabolites were measured by liquid chromatography-tandem mass spectrometry. Their serum concentrations were related to the age of the patients. To circumvent effects of cytochrome (CYP) 2D6 polymorphisms we also examined these correlations exclusively in homozygous extensive metabolizers. The concentrations of 4OHNDtam, tamoxifen, NDtam (N-desmethyltamoxifen), and NDDtam (N-desdimethyltamoxifen) were positively correlated to age (n = 151, p = 0.017, 0.045, 0.011, and 0.001 respectively). When exclusively studying the CYP2D6 homozygous extensive metabolizers (n = 86) the correlation between 4OHNDtam and age increased (p = 0.008). Up to tenfold inter-patient variation in the serum concentrations was observed. The median (inter-patient range) concentration of 4OHNDtam in the age groups 30-49, 50-69, and >69 years were 65 (24-89), 116 (25-141), and 159 (26-185) ng/ml, respectively. We conclude that the serum concentrations of 4OHNDtam (endoxifen), tamoxifen, and its demethylated metabolites increase with age during steady-state tamoxifen treatment. This may represent an additional explanation why studies on the effects of CYP2D6 polymorphisms on outcome in tamoxifen-treated breast cancer patients have been inconsistent. The observed high inter-patient range

  14. 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. PMID:26427451

  15. 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.

  16. Interpreting the CYP2D6 Results From the International Tamoxifen Pharmacogenetics Consortium

    PubMed Central

    Province, MA; Altman, RB; Klein, TE

    2014-01-01

    Meta-analysis of the entire analyzable cohort of 4,935 tamoxifen-treated breast cancer patients by the International Tamoxifen Pharmacogenetics Consortium (ITPC) (criterion 3) revealed no CYP2D6 effect on outcomes but strong heterogeneity across sites.1 However, a post hoc–defined subgroup (criterion 1: postmenopausal, estrogen receptor positive, receiving 20 mg/day tamoxifen for 5 years; n = 1,996) did find statistically significant effect of CYP2D6 on both invasive disease–free survival as well as breast cancer–free interval, with little site heterogeneity. How should we interpret these discrepant findings? PMID:25056393

  17. 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

  18. 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

  19. 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

  20. Intravitreal bevacizumab monotherapy for choroidal neovascularisation secondary to choroidal osteoma.

    PubMed

    Papastefanou, V P; Pefkianaki, M; Al Harby, L; Arora, A K; Cohen, V M L; Andrews, R M; Sagoo, M S

    2016-06-01

    PurposeThe purpose of this study is to present the outcomes of a series of patients with choroidal neovascular membrane (choroidal neovascularisation (CNV)) secondary to a choroidal osteoma undergoing anti-VEGF monotherapy.Patients and methodsRetrospective series of patients with choroidal neovascularization secondary to choroidal osteoma. All patients underwent clinical and imaging assessment (fundus photo, B-scan ultrasonography, fluorescein angiography, and optical coherence tomography-where available), and were managed with intravitreal anti-VEGF injections (Bevacizumab). Visual acuity and central retinal thickness were recorded pre treatment and at the end of the follow-up period.ResultsEight patients were included in this study. Of this, 6/8 had predominantly classic or classic and 2/8 patients had minimally classic or occult CNV. Each patient received 3-10 injections of bevacizumab. Median follow-up was 9 months (3-15 months). Visual acuity improved in 5 patients, by 2-6 Snellen lines. CNV completely regressed in 5 cases and partially regressed in 3 cases. Mean CRT reduction was 122 μm (6 to -230 μm).ConclusionIntravitreal bevacizumab can be an effective treatment modality in the management of vision threatening CNV secondary to choroidal osteoma. PMID:27034203

  1. Efficacy and Safety of Metronidazole Monotherapy versus Vancomycin Monotherapy or Combination Therapy in Patients with Clostridium difficile Infection: A Systematic Review and Meta-Analysis

    PubMed Central

    Li, Rui; Lu, Laichun; Lin, Yu; Wang, Mingxia; Liu, Xin

    2015-01-01

    Background Clostridium difficile infection (CDI) has become a global epidemiological problem for both hospitalized patients and outpatients. The most commonly used drugs to treat CDI are metronidazole and vancomycin. The aim of this study was to compare the efficacy and safety of metronidazole monotherapy with vancomycin monotherapy and combination therapy in CDI patients. Methods A comprehensive search without publication status or other restrictions was conducted. Studies comparing metronidazole monotherapy with vancomycin monotherapy or combination therapy in patients with CDI were considered eligible. Meta-analysis was performed using the Mantel-Haenszel fixed-effects model, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated and reported. Results Of the 1910 records identified, seventeen studies from thirteen articles (n = 2501 patients) were included. No statistically significant difference in the rate of clinical cure was found between metronidazole and vancomycin for mild CDI (OR = 0.67, 95% CI (0.45, 1.00), p = 0.05) or between either monotherapy and combination therapy for CDI (OR = 1.07, 95% CI (0.58, 1.96), p = 0.83); however, the rate of clinical cure was lower for metronidazole than for vancomycin for severe CDI (OR = 0.46, 95% CI (0.26, 0.80), p = 0.006). No statistically significant difference in the rate of CDI recurrence was found between metronidazole and vancomycin for mild CDI (OR = 0.99, 95% CI (0.40, 2.45), p = 0.98) or severe CDI (OR = 0.98, 95% CI (0.63, 1.53), p = 0.94) or between either monotherapy and combination therapy for CDI (OR = 0.91, 95% CI (0.66, 1.26), p = 0.56). In addition, there was no significant difference in the rate of adverse events (AEs) between metronidazole and vancomycin (OR = 1.18, 95% CI (0.80, 1.74), p = 0.41). In contrast, the rate of AEs was significantly lower for either monotherapy than for combination therapy (OR = 0.30, 95% CI (0.17, 0.51), p<0.0001). Conclusions Metronidazole and

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

    PubMed Central

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

    2014-01-01

    Background: Randomised trials of tamoxifen versus placebo indicate that tamoxifen reduces breast cancer risk by approximately 33%, yet uptake is low. Approximately 10% of women in our clinic entered the IBIS-I prevention trial. We assess the uptake of tamoxifen in a consecutive series of premenopausal women not in a trial and explore the reasons for uptake through interviews. Methods: All eligible women between 33 and 46 years at ⩾17% lifetime risk of breast cancer and undergoing annual mammography in our service were invited to take a 5-year course of tamoxifen. Reasons for accepting (n=15) or declining (n=15) were explored using semi-structured interviews. Results: Of 1279 eligible women, 136 (10.6%) decided to take tamoxifen. Women >40 years (74 out of 553 (13.4%)) and those at higher non-BRCA-associated risk were more likely to accept tamoxifen (129 out of 1109 (11.6%)). Interviews highlighted four themes surrounding decision making: perceived impact of side effects, the impact of others' experience on beliefs about tamoxifen, tamoxifen as a ‘cancer drug', and daily reminder of cancer risk. Conclusions: Tamoxifen uptake was similar to previously ascertained uptake in a randomised controlled trial (IBIS-I). Concerns were similar in women who did or did not accept tamoxifen. Decision making appeared to be embedded in the experience of significant others. PMID:24594998

  3. 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

  4. 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

  5. A peptide derived from alpha-fetoprotein prevents the growth of estrogen-dependent human breast cancers sensitive and resistant to tamoxifen.

    PubMed

    Bennett, James A; Mesfin, Fassil B; Andersen, Thomas T; Gierthy, John F; Jacobson, Herbert I

    2002-02-19

    An 8-mer peptide (EMTOVNOG) derived from alpha-fetoprotein was compared with tamoxifen for activity against growth of human breast cancer xenografts implanted in immune-deficient mice. Both peptide and tamoxifen prevented growth of estrogen-receptor-positive MCF-7 and T47D human breast cancer xenografts. A subline of MCF-7, made resistant to tamoxifen by a 6-month exposure to this drug in culture, was found to be resistant to tamoxifen in vivo. Peptide completely prevented the xenograft growth of this tamoxifen-resistant subline of MCF-7. Neither peptide nor tamoxifen was effective in slowing the xenograft growth of the estrogen-receptor-negative MDA-MB-231 human breast cancer. A worrisome side effect of tamoxifen is its hypertrophic effect on the uterus. In this study, tamoxifen was shown to stimulate the growth of the immature mouse uterus in vivo, and the peptide significantly inhibited tamoxifen's uterotrophic effect. The mechanism of action of peptide is different from that of tamoxifen in that the peptide does not interfere with the binding of [(3)H]estradiol to the estrogen receptor. In conclusion, alpha-fetoprotein-derived peptide appears to be a novel agent that interferes with the growth of tamoxifen-sensitive as well as tamoxifen-resistant estrogen-receptor-positive human breast cancers; it inhibits the uterotrophic side effect of tamoxifen and, thus, it may be useful in combination with or in place of tamoxifen for treatment of estrogen-receptor-positive human breast cancers. PMID:11830647

  6. Polysaccharides: Candidates of promising vaccine adjuvants.

    PubMed

    Li, Pingli; Wang, Fengshan

    2015-04-01

    Aluminium-based adjuvants remain the only adjuvants approved for human use in the USA for over 80 years because of alum's simplicity, tolerability, safety and cost-efficiency. Recent development of vaccines, especially the increasing applications of recombinant subunit and synthetic vaccines, makes aluminium adjuvants cannot stimulate enough immunity to the antigens, since aluminium adjuvants can only induce Th2 type immune responses. So, novel adjuvants are urgent to make up the disadvantages of aluminium adjuvants. However, some major hurdles need to be overcome, not only the scientific knowledge of adjuvants but also unacceptable side-effects and toxicity. A number of carbohydrate-based polysaccharides from plant, bacterial, yeast and synthetic sources can act as pathogen-associated molecular patterns (PAMPs) and recognize pattern recognition receptors (PRRs) on immune cells, followed by triggering innate immunity and regulating adaptive immunity. What is more, polysaccharides are safe and biodegradable without tissue deposits as observed in aluminium adjuvants. Therefore, polysaccharide-based compounds and formulations are potential vaccine adjuvant candidates. Here, we mainly review polysaccharide-based adjuvants investigated in recent years. PMID:25994059

  7. 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.

  8. 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.

  9. Concurrent tamoxifen-related Müllerian adenofibromas in uterus and ovary

    PubMed Central

    Shi, Haiyan; Chen, Xiaoduan; Lv, Bingjian; Zhang, Xiaofei

    2015-01-01

    Tamoxifen is a widely used in anti-oestrogen treatment of breast cancer. Previous reports showed that tamoxifen is associated with proliferative endometrial lesions. We herein reported an unusual case of concurrent hyperplastic lesions in the uterine cavity and right ovary in a 45-year-old woman with tamoxifen therapy. Regular vaginal ultrasonography showed the progressive endometrial thickening and right ovary enlargement during the period of drug use. Both lesions in the uterine cavity and right ovary showed characteristics resembling that of Müllerian adenofibroma. There were also foci of endometriosis in her bilateral ovarian surfaces. We suggest that women taking tamoxifen with a known history of endometriosis should be followed with transvaginal ultrasonography periodically. PMID:26823898

  10. 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

  11. Doppler flow evaluation of pathologic endometrial conditions in postmenopausal breast cancer patients treated with tamoxifen.

    PubMed

    Tepper, R; Cohen, I; Altaras, M; Shapira, J; Cordoba, M; Dror, Y; Beyth, Y

    1994-08-01

    A prospective pilot study was conducted to evaluate the usefulness of uterine artery blood flow in the detection of various pathologic endometrial conditions in 39 asymptomatic postmenopausal breast cancer patients who were treated with tamoxifen. No specific pattern was seen for the uterine artery pulsatility index values in the tamoxifen-treated patients that could be related to any specific endometrial lesions, nor were any specific changes observed in the pulsatility index value with increasing severity of the pathologic endometrial conditions. Similarly, no correlation was found between ultrasonographically measured endometrial widths and uterine artery pulsatility index values. Thus, although pulsed Doppler flow ultrasonography has been shown previously to be effective in the detection of uterine cancer in non-tamoxifen-treated post-menopausal patients, it probably does not contribute to the assessment of endometrial lesions in post-menopausal breast cancer patients treated with tamoxifen. PMID:7933033

  12. Adenomyosis in postmenopausal breast cancer patients treated with tamoxifen: a new entity?

    PubMed

    Cohen, I; Beyth, Y; Tepper, R; Figer, A; Shapira, J; Cordoba, M; Yigael, D; Altaras, M M

    1995-07-01

    Between September 1, 1989 and October 31, 1994, 173 postmenopausal breast cancer women on tamoxifen treatment were followed up in the authors' institutions. During this period, 14 (8.1%) underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for various indications. Eight (57.1%) were found to have adenomyosis, of whom one had a large fundal adenomyotic lump and the other seven patients had two to four small microscopic foci of adenomyosis. In this study, the rate of adenomyosis described among those postmenopausal breast cancer patients treated with tamoxifen is nearly three to four times higher than the rate reported in the literature for pre- and postmenopausal women. There is no previous reported increased incidence of adenomyosis in postmenopausal breast cancer patients treated with tamoxifen. Thus, it is suggested that the prolonged and unopposed estrogen-like stimulation by tamoxifen may play a causal role rather than be a casual factor in the development of this pathologic entity. PMID:7789896

  13. 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.

  14. Individualization of tamoxifen therapy: much more than just CYP2D6 genotyping.

    PubMed

    Binkhorst, Lisette; Mathijssen, Ron H J; Jager, Agnes; van Gelder, Teun

    2015-03-01

    Clinical response to tamoxifen varies widely among women treated with this drug for hormone receptor-positive breast cancer. The principal active metabolite - endoxifen - is generated through hepatic metabolism of tamoxifen, with key roles for cytochrome P450 (CYP) CYP2D6 and CYP3A. By influencing endoxifen formation, genetic variants of CYP2D6 may affect response to tamoxifen. After a decade of research, examining the effects of CYP2D6 genetic variants on tamoxifen efficacy, there is still no agreement on the clinical utility of CYP2D6 genotype as biomarker for the prediction of breast cancer outcome, because studies revealed conflicting results. However, tamoxifen metabolism is complex and involves several other drug-metabolizing enzymes. Genetic variants of other CYP enzymes, including CYP3A4 and CYP2C9/19, as well as co-medication interfering with the metabolic activity of CYP2D6 and CYP3A4 have been shown to affect endoxifen concentrations and may also contribute to the variability in response to tamoxifen. Phenotyping strategies can predict endoxifen exposure more accurately than CYP2D6 genotype, but do not take into account all factors influencing endoxifen exposure. Therapeutic drug monitoring (TDM) is likely to be the optimal strategy for individualization of tamoxifen treatment. According to a growing amount of literature, endoxifen concentration seems to be a predictor of clinical outcome. The relationship between endoxifen levels and breast cancer outcomes has to be replicated and confirmed and the value of TDM should be evaluated in prospective clinical trials. Caution is advised regarding the concomitant use of medications which could interact with tamoxifen, including inhibitors and inducers of CYP enzymes. PMID:25618289

  15. Tamoxifen Inhibits ER-negative Breast Cancer Cell Invasion and Metastasis by Accelerating Twist1 Degradation

    PubMed Central

    Ma, Gang; He, Jianjun; Yu, Yang; Xu, Yixiang; Yu, Xiaobin; Martinez, Jarrod; Lonard, David M.; Xu, Jianming

    2015-01-01

    Twist1 is a transcription factor driving epithelial-mesenchymal transition, invasion and metastasis of breast cancer cells. Mice with germ-line Twist1 knockout are embryonic lethal, while adult mice with inducible Twist1 knockout have no obvious health problems, suggesting that Twist1 is a viable therapeutic target for the inhibition of invasion and metastasis of breast cancer in adult patients. In this study, we expressed a luciferase protein or a Twist1-luciferase fusion protein in HeLa cells as part of a high throughput system to screen 1280 compounds in the Library of Pharmacologically Active Compounds (LOPAC) from Sigma-Aldrich for their effects on Twist1 protein expression. One of the most interesting compounds identified is tamoxifen, a selective estrogen receptor (ER) modulator used to treat ER-positive breast cancer. Tamoxifen treatment significantly accelerated Twist1 degradation in multiple cell lines including HEK293 human kidney cells, 4T1 and 168FARN mouse mammary tumor cells with either ectopically or endogenously expressed Twist1. Tamoxifen-induced Twist1 degradation could be blocked by the MG132 proteasome inhibitor, suggesting that tamoxifen induces Twist1 degradation through the ubiquitination-proteasome pathway. However, tamoxifen-induced Twist1 degradation was independent of Twist1 mRNA expression, estrogen signaling and MAPK-mediated Twist1 phosphorylation in these cells. Importantly, tamoxifen also significantly inhibited invasive behavior in Matrigel and lung metastasis in SCID-bg mice of ER-negative 4T1 mammary tumor cells, which depend on endogenous Twist1 to invade and metastasize. These results indicate that tamoxifen can significantly accelerate Twist1 degradation to suppress cancer cell invasion and metastasis, suggesting that tamoxifen can be used not only to treat ER-positive breast cancers but also to reduce Twist1-mediated invasion and metastasis in ER-negative breast cancers. PMID:25892968

  16. Tamoxifen inhibits ER-negative breast cancer cell invasion and metastasis by accelerating Twist1 degradation.

    PubMed

    Ma, Gang; He, Jianjun; Yu, Yang; Xu, Yixiang; Yu, Xiaobin; Martinez, Jarrod; Lonard, David M; Xu, Jianming

    2015-01-01

    Twist1 is a transcription factor driving epithelial-mesenchymal transition, invasion and metastasis of breast cancer cells. Mice with germ-line Twist1 knockout are embryonic lethal, while adult mice with inducible Twist1 knockout have no obvious health problems, suggesting that Twist1 is a viable therapeutic target for the inhibition of invasion and metastasis of breast cancer in adult patients. In this study, we expressed a luciferase protein or a Twist1-luciferase fusion protein in HeLa cells as part of a high throughput system to screen 1280 compounds in the Library of Pharmacologically Active Compounds (LOPAC) from Sigma-Aldrich for their effects on Twist1 protein expression. One of the most interesting compounds identified is tamoxifen, a selective estrogen receptor (ER) modulator used to treat ER-positive breast cancer. Tamoxifen treatment significantly accelerated Twist1 degradation in multiple cell lines including HEK293 human kidney cells, 4T1 and 168FARN mouse mammary tumor cells with either ectopically or endogenously expressed Twist1. Tamoxifen-induced Twist1 degradation could be blocked by the MG132 proteasome inhibitor, suggesting that tamoxifen induces Twist1 degradation through the ubiquitination-proteasome pathway. However, tamoxifen-induced Twist1 degradation was independent of Twist1 mRNA expression, estrogen signaling and MAPK-mediated Twist1 phosphorylation in these cells. Importantly, tamoxifen also significantly inhibited invasive behavior in Matrigel and lung metastasis in SCID-bg mice of ER-negative 4T1 mammary tumor cells, which depend on endogenous Twist1 to invade and metastasize. These results indicate that tamoxifen can significantly accelerate Twist1 degradation to suppress cancer cell invasion and metastasis, suggesting that tamoxifen can be used not only to treat ER-positive breast cancers but also to reduce Twist1-mediated invasion and metastasis in ER-negative breast cancers. PMID:25892968

  17. Transcriptional and morphological effects of tamoxifen on the early development of zebrafish (Danio rerio).

    PubMed

    Xia, Liang; Zheng, Liang; Zhou, Jun Liang

    2016-06-01

    Tamoxifen is a widely used anticancer drug with both an estrogen agonist and antagonist effect. This study focused on its endocrine disrupting effect, and overall environmental significance. Zebrafish embryos were exposed to different concentrations (0.5, 5, 50 and 500 µg l(-1) ) of tamoxifen for 96 h. The results showed a complex effect of tamoxifen on zebrafish embryo development. For the 500 µg l(-1) exposure group, the heart rate was decreased by 20% and mild defects in caudal fin and skin were observed. Expressions of a series of genes related to endocrine and morphological changes were subsequently tested through quantitative real-time polymerase chain reaction. Bisphenol A as a known estrogen was also tested as an endocrine-related comparison. Among the expression of endocrine-related genes, esr1, ar, cyp19a1b, hsd3b1 and ugt1a1 were all increased by tamoxifen exposure, similar to bisphenol A. The cyp19a1b is a key gene that controls estrogen synthesis. Exposure to 0.5, 5, 50 and 500 µg l(-1) of tamoxifen caused upregulation of cyp19a1b expression to 152%, 568%, 953% and 2024% compared to controls, higher than the effects from the same concentrations of bisphenol A treatment, yet vtg1 was suppressed by 24% from exposure to 500 µg l(-1) tamoxifen. The expression of metabolic-related genes such as cyp1a, cyp1c2, cyp3a65, gpx1a, gstp1, gsr and genes related to observed morphological changes such as krt17 were also found to be upregulated by high concentrations of tamoxifen. These findings indicated the potential environmental effect of tamoxifen on teleost early development. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26584595

  18. 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

  19. Endometrial evaluation by ultrasonography, hysteroscopy and histopathology in cases of breast carcinoma on Tamoxifen therapy

    PubMed Central

    Jindal, Alka; Mohi, Manjit K.; Kaur, Manjeet; Kaur, Balwinder; Singla, Risham; Singh, Shaunik

    2015-01-01

    Introduction: Tamoxifen, a nonsteroidal antiestrogenic agent, is used widely as adjunctive therapy for women with breast cancer. Most studies have found that the increased relative risk of developing endometrial cancer for women taking Tamoxifen is two to three times higher than that of an age-matched population. So we designed this study to assess the endometrial status in patients taking Tamoxifen for breast carcinoma. Material and Methods: The study was conducted at Govt. Medical College and Rajindra Hospital, Patiala, India. A total of 50 patients of Ca Breast taking Tamoxifen were selected as per study criterion and TVS performed. If endometrial thickness was more than 5 mm hysteroscopy and endometrial HPE was done and data analysed. Results: On ultrasonography 35 patients (70%) had an endometrial thickness up to 5 mm. 15 patients (30%) had an endometrial thickness more than 5mm. Out of these, 11 patients, i.e. 22% of total, had an endometrial thickness of 5.1 to 10 mm and 2 patients, i.e. 4% of total had an endometrial thickness of more than 20 mm. Hysteroscopy was done on 11 patients. Out of these 8 patients had a normal hysteroscopic appearance whereas 3 patients had an abnormal hysteroscopic picture. Endometrial HPE of these 11 patients revealed 2 patients had secretory changes, 1 had polyp change, 1 had atrophic endometrium, 3 had simple endometrial hyperplasia, 1 had endometrial adenocarcinoma and 4 patients were reported to have scanty curetting. Conclusion: The duration of Tamoxifen therapy turned out to have a relationship with the incidence of endometrial carcinoma (P < 0.0001). Also, a relationship was observed between the duration of Tamoxifen therapy and symptom status of the patients (P < 0.0001). This correlation did not extend to duration of Tamoxifen therapy and endometrial thickness. (P = 0.190). This correlation did not extend to duration of Tamoxifen therapy and endometrial thickness. (P = 0.190). PMID:26167055

  20. 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

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

    PubMed Central

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

    2015-01-01

    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

  2. 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

  3. 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

  4. Breast anticancer drug tamoxifen and its metabolites bind tRNA at multiple sites.

    PubMed

    Bourassa, P; Thomas, T J; Bariyanga, J; Tajmir-Riahi, H A

    2015-01-01

    The binding sites of breast anticancer drug tamoxifen and its metabolites with tRNA were located by FTIR, CD, UV-visible, and fluorescence spectroscopic methods and molecular modeling. Structural analysis showed that tamoxifen and its metabolites bind tRNA at several binding sites with overall binding constants of K(tam-tRNA) = 5.2 (± 0.6) × 10(4) M(-1), K(4-hydroxytam-tRNA) = 6.5 ( ± 0.5) × 10(4) M(-1) and K(endox-tRNA) = 1.3 (± 0.2) × 10(4) M(-1). The number of binding sites occupied by drug molecules on tRNA were 1 (tamoxifen), 0.8 (4-hydroxitamoxifen) and 1.2 (endoxifen). Docking showed the participation of several nucleobases in drug-tRNA complexes with the free binding energy of -4.31 (tamoxifen), -4.45 (4-hydroxtamoxifen) and -4.38 kcal/mol (endoxifen). The order of binding is 4-hydroxy-tamoxifen > tamoxifen > endoxifen. Drug binding did not alter tRNA conformation from A-family structure, while biopolymer aggregation occurred at high drug concentration. PMID:25263468

  5. Locating the binding sites of antitumor drug tamoxifen and its metabolites with DNA.

    PubMed

    Bourassa, P; Thomas, T J; Tajmir-Riahi, H A

    2014-07-01

    We located the binding sites of antitumor drugs tamoxifen, 4-hydroxytamoxifen and endoxifen with calf-thymus DNA. FTIR, CD, UV-vis and fluorescence spectroscopic methods as well as molecular modeling were used to characterize the drug binding sites, binding constant and the effect of drug binding on DNA stability and conformation. Structural analysis showed that tamoxifen and its metabolites bind DNA via hydrophobic and hydrophilic interactions with overall binding constants of K(tam-DNA)=3.5 (±0.2)×10⁴ M⁻¹, K(4-hydroxytam-DNA)=3.3 (±0.4) × 10⁴ M⁻¹ and K(endox)-DNA=2.8 (±0.8)×10⁴ M⁻¹. The number of binding sites occupied by drug is 1 (tamoxifen), 0.8 (4-hydroxitamoxifen) and 1.2 (endoxifen). Docking showed the participation of several nucleobases in drug-DNA complexes with the free binding energy of -3.85 (tamoxifen), -4.18 (4-hydroxtamoxifen) and -3.74 kcal/mol (endoxifen). The order of binding is 4-hydroxy-tamoxen>tamoxifen>endoxifen. Drug binding did not alter DNA conformation from B-family structure, while major biopolymer aggregation occurred at high drug concentrations. The drug binding mode is correlated with the mechanism of action of antitumor activity of tamoxifen and its metabolites. PMID:24682017

  6. 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

  7. Tamoxifen DNA damage detected in human endometrium using accelerator mass spectrometry.

    PubMed

    Martin, Elizabeth A; Brown, Karen; Gaskell, Margaret; Al-Azzawi, Farook; Garner, R Colin; Boocock, David J; Mattock, Elizabeth; Pring, David W; Dingley, Karen; Turteltaub, Kenneth W; Smith, Lewis L; White, Ian N H

    2003-12-01

    This study was aimed to establish whether tamoxifen binds irreversibly to uterine DNA when given to women. Patients were given a single therapeutic dose of [(14)C]tamoxifen citrate orally (20 mg, 0.37 or 1.85 MBq) approximately 18 h prior to hysterectomy or breast surgery. Nonmalignant uterine tissue was separated into myometrium and endometrium. DNA and protein were isolated and bound radiolabel determined by the sensitive technique of accelerator mass spectrometry. Levels of irreversible DNA binding of tamoxifen in the endometrium of treated patients were 237 +/- 77 adducts/10(12) nucleotides (mean +/- SE, n = 10). In myometrial tissues, a similar extent of DNA binding was detected (492 +/- 112 adducts/10(12) nucleotides). Binding of tamoxifen to endometrial and myometrial proteins was 10 +/- 3 and 20 +/- 4 fmol/mg, respectively. In breast tissue, sufficient DNA could not be extracted but protein binding was an order of magnitude higher than that seen with endometrial proteins (358 +/- 81 fmol/mg). These results demonstrate that after oral administration, tamoxifen forms adducts in human uterine DNA but at low numbers relative to those previously reported in women after long-term tamoxifen treatment where levels, when detected, ranged from 15000 to 130000 adducts/10(12) nucleotides. Our findings support the hypothesis that the low level of DNA adducts in human uterus is unlikely to be involved with endometrial cancer development. PMID:14679010

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

    PubMed Central

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

    2012-01-01

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

  9. 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

  10. Adjuvant therapy use among Appalachian breast cancer survivors

    PubMed Central

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

    2015-01-01

    Abstract 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

  11. 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

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

    PubMed Central

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

    2006-01-01

    Breast carcinoma is the most common malignancy among women and it has a major impact on mortality. Studies of primary chemoprevention with tamoxifen have generated high expectations and considerable success rates. The efficacy of lower doses of tamoxifen is similar to that seen with a standard dose of the drug, and there has been a reduction in healthcare costs and side effects. The immune reaction to monoclonal antibody Ki-67 (MIB-1) and the expression of estrogen receptors (1D5) and progesterone receptors (PgR 636) in breast carcinoma were studied in patients treated with 10 mg of tamoxifen for a period of 14 days. A prospective randomized clinical trial was conducted with 38 patients divided into two groups: Group A: N = 20 (control group-without medication) and Group B: N = 18 (tamoxifen/10 mg/day for 14 days). All patients signed an informed consent term previously approved by both institutions. Patients underwent incisional biopsy before treatment and 14 days later a tumor tissue sample was obtained during surgical treatment. Positivity was quantitatively assessed, counting at least 1.000 cells per slide. For statistical data analysis, a Wilcoxon non-parametric test was used, and α was set at 5%. Both groups (A and B) were considered homogeneous regarding control variables. In Group A (control), there was no statistically significant reduction in Ki-67 (MIB-1) (p = 0.627), estrogen receptor (1D5) (p = 0.296) and progesterone receptor positivity (PgR 636) (p = 0.381). In Group B (tamoxifen 10 mg/day), the mean percentage of nuclei stained by Ki-67 (MIB-1) was 24.69% before and 10.43% after tamoxifen treatment. Mean percentage of nuclei stained by estrogen receptor (1D5) was 59.53% before and 25.99% after tamoxifen treatment. Mean percentage of nuclei stained by progesterone receptor (PgR 636), was 59.34 before and 29.59% after tamoxifen treatment. A statistically significant reduction was found with the three markers (p < 0.001). Tamoxifen significantly

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

    PubMed

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

    2014-07-01

    The anti-estrogenic effect of tamoxifen is suggested to be mainly attributable to its metabolite (Z)-endoxifen, and a minimum therapeutic threshold for (Z)-endoxifen in serum has been proposed. The objective of this research was to establish the relationship between dried blood spot (DBS) and serum concentrations of tamoxifen and (Z)-endoxifen to allow the use of DBS sampling, a simple and patient-friendly alternative to venous sampling, in clinical practice. Paired DBS and serum samples were obtained from 50 patients using tamoxifen and analyzed using HPLC-MS/MS. Serum concentrations were calculated from DBS concentrations using the formula calculated serum concentration = DBS concentration/([1-haematocrit (Hct)] + blood cell-to-serum ratio × Hct). The blood cell-to-serum ratio was determined ex vivo by incubating a batch of whole blood spiked with both analytes. The average Hct for female adults was imputed as a fixed value. Calculated and analyzed serum concentrations were compared using weighted Deming regression. Weighted Deming regression analysis comparing 44 matching pairs of DBS and serum samples showed a proportional bias for both analytes. Serum concentrations were calculated using [Tamoxifen] serum, calculated  = [Tamoxifen] DBS /0.779 and [(Z)-Endoxifen] serum, calculated = [(Z)-Endoxifen] DBS /0.663. Calculated serum concentrations were within 20 % of analyzed serum concentrations in 84 and 100 % of patient samples for tamoxifen and (Z)-endoxifen, respectively. In conclusion, DBS concentrations of tamoxifen and (Z)-endoxifen were equal to serum concentrations after correction for Hct and blood cell-to-serum ratio. DBS sampling can be used in clinical practice. PMID:24859000

  14. 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.

  15. 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

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

    PubMed

    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

  17. 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

  18. 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

  19. Fluvoxamine monotherapy for psychotic depression: the potential role of sigma-1 receptors

    PubMed Central

    2009-01-01

    Background Psychotic depression is a clinical subtype of major depressive disorder. A number of clinical studies have demonstrated the efficacy of the combination of an antidepressant (for example, a tricyclic antidepressant or selective serotonin reuptake inhibitor (SSRI)) and an atypical antipsychotic or electroconvulsive therapy in treating psychotic depression. In some cases, the clinician or patient may prefer to avoid antipsychotic drugs altogether because of the risk of extrapyramidal side effects (EPS) in patients with psychotic depression treated with these drugs. Methods We report five cases where fluvoxamine monotherapy was effective in the patients with psychotic depression. Results The scores on the Hamilton Depression (HAM-D) scale and the Brief Psychiatric Rating Scale (BPRS) in the five patients with psychotic depression were reduced after fluvoxamine monotherapy. Conclusion Doctors should consider fluvoxamine monotherapy as an alternative approach in treating psychotic depression because it avoids the risk of EPS from antipsychotic drugs. PMID:20025739

  20. 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

  1. 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

  2. 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

  3. Magnetic nanoparticle hyperthermia as an adjuvant cancer therapy with chemotherapy

    NASA Astrophysics Data System (ADS)

    Petryk, Alicia Ailie

    Magnetic nanoparticle hyperthermia (mNPH) is an emerging cancer therapy which has shown to be most effective when applied in the adjuvant setting with chemotherapy, radiation or surgery. Although mNPH employs heat as a primary therapeutic modality, conventional heat may not be the only cytotoxic effect. As such, my studies have focused on the mechanism and use of mNPH alone and in conjunction with cisplatinum chemotherapy in murine breast cancer cells and a related in vivo model. MNPH was compared to conventional microwave tumor heating, with results suggesting that mNPH (mNP directly injected into the tumor and immediately activated) and 915 MHz microwave hyperthermia, at the same thermal dose, result in similar tumor regrowth delay kinetics. However, mNPH shows significantly less peri-tumor normal tissue damage. MNPH combined with cisplatinum also demonstrated significant improvements in regrowth delay over either modality applied as a monotherapy. Additional studies demonstrated that a relatively short tumor incubation time prior to AMF exposure (less than 10 minutes) as compared to a 4-hour incubation time, resulted in faster heating rates, but similar regrowth delays when treated to the same thermal dose. The reduction of heating rate correlated well with the observed reduction in mNP concentration in the tumor observed with 4 hour incubation. The ability to effectively deliver cytotoxic mNPs to metastatic tumors is the hope and goal of systemic mNP therapy. However, delivering relevant levels of mNP is proving to be a formidable challenge. To address this issue, I assessed the ability of cisplatinum to simultaneously treat a tumor and improve the uptake of systemically delivered mNPs. Following a cisplatinum pretreatment, systemic mNPs uptake was increased by 3.1 X, in implanted murine breast tumors. Additional in vitro studies showed the necessity of a specific mNP/ Fe architecture and spatial relation for heat-based cytotoxicity in cultured cells.

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

    PubMed

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

    2016-07-01

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

  5. 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. PMID:25643697

  6. 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.

  7. Tamoxifen and the Risk of Ovarian Cancer in BRCA1 Mutation Carriers

    PubMed Central

    Vicus, Danielle; Rosen, Barry; Lubinski, Jan; Domchek, Susan; Kauff, Noah D.; Lynch, Henry T.; Isaacs, Claudine; Tung, Nadine; Sun, Ping; Narod, Steven A.

    2013-01-01

    Objective BRCA1 mutation carriers have a high rate of both breast and ovarian cancer. Tamoxifen is a selective estrogen receptor modulator (SERM), which is used for the treatment of primary breast cancer and for the prevention of contralateral breast cancer. Our objective is to assess if tamoxifen treatment is associated with an increase in the subsequent risk of ovarian cancer among women with a BRCA1 mutation. Methods A matched case-control study was performed. Cases were 154 women with ovarian cancer and a previous history of breast cancer. Controls were 560 women with no ovarian cancer and a history of breast cancer. All cases and controls carry a deleterious BRCA1 mutation. Cases and controls were matched for year of birth, age at diagnosis of breast cancer and country of residence. The effect of tamoxifen treatment on the risk of subsequent ovarian cancer was estimated using conditional logistic regression. Results The unadjusted odds ratio for ovarian cancer, given previous tamoxifen treatment was 0.89 (95% CI 0.54–1.49, p = 0.66). After adjusting for other treatments, the odds ratio was 0.78 (95% CI 0.46–1.33, p = 0.36). Conclusion Tamoxifen treatment for breast cancer does not appear to increase the risk of ovarian cancer in BRCA1 mutation carriers. PMID:19577280

  8. Effect of Tamoxifen and Raloxifene on the Proliferative Activity of the Breast Epithelium in Premenopausal Women*

    PubMed Central

    Lucato, Miliana T; Freitas-Junior, Ruffo; Moreira, Marise AR; Bernardes-Junior, Júlio RM; Pinto, Sebastião A; Paulinelli, Regis R; Soares, Leonardo R

    2015-01-01

    OBJECTIVES To compare the effects of tamoxifen and raloxifene on the proliferative activity of normal breast tissue in premenopausal women as measured by Ki-67/MIB-1 expression. STUDY DESIGN A total of 48 women with benign breast nodules and a recommendation for surgical removal of the lesion took part in this study. They were randomized to use tamoxifen or raloxifene for 22 days, after which they were submitted to surgery. During the surgical procedure, a 1-cm fragment of normal breast tissue was removed to study Ki-67 expression. RESULTS The mean percentage ratios between immunolabeled and non-labeled cells were 2.02 ± 1.09 and 3.13 ± 3.23 for the tamoxifen and raloxifene groups, respectively. There was no statistically significant difference between the tamoxifen (n = 16) and raloxifene (n = 14) groups in relation to the immunohistochemical analysis of Ki-67 (P = 0.205). CONCLUSION The results of this study showed no difference between tamoxifen and raloxifene with respect to the potential of these drugs to reduce the proliferative activity of the normal breast epithelium in premenopausal women. PMID:25861235

  9. 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

  10. 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

  11. 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

  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. 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

  14. 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

  15. 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

  16. Tamoxifen reduces fat mass by boosting reactive oxygen species

    PubMed Central

    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

  17. Pharmacokinetic drug interactions between ondansetron and tamoxifen in female Sprague-Dawley rats with DMBA-induced mammary tumor.

    PubMed

    Yang, Si Hyung; Suh, Jung Hwa; Lee, Myung Gull; Kim, So Hee

    2013-02-01

    Tamoxifen, which is used to treat breast cancer, and ondansetron, used for the treatment of chemotherapy-induced nausea, are commonly metabolized via cytochrome P450 (CYP) 2D subfamily and 3A1/2 in rats, as in humans. This study was conducted to investigate the pharmacokinetic interactions between ondansetron and tamoxifen after intravenous and oral administration of ondansetron (both 8 mg/kg) and/or tamoxifen (2 and 10 mg/kg for intravenous and oral administration, respectively), in rats bearing 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammarian tumors (DMBA rats), used as an animal model of human breast cancer. The total area under the plasma concentration-time curve, from time zero to infinity (AUC) of tamoxifen was significantly greater after both intravenous and oral administration with ondansetron, compared to that after administration of tamoxifen-alone. The hepatic and intestinal metabolism of tamoxifen in DMBA rats was inhibited by ondansetron. Taken together, the significant increase in tamoxifen AUC in DMBA rats after intravenous or oral administration with ondansetron may be attributed to non-competitive hepatic (intravenous) and competitive intestinal (oral) inhibition of CYP2D subfamily- and 3A1/2-mediated tamoxifen metabolism by ondansetron. PMID:23393344

  18. 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...

  19. 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

  20. 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

  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. Combination therapy with tamoxifen and amphotericin B in experimental cutaneous leishmaniasis.

    PubMed

    Trinconi, Cristiana T; Reimão, Juliana Q; Yokoyama-Yasunaka, Jenicer K U; Miguel, Danilo C; Uliana, Silvia R B

    2014-05-01

    Leishmaniasis chemotherapy remains very challenging. The high cost of active drugs, along with the severity of their side effects and the increasing failure rate of the current therapeutic schemes, calls for the discovery of new active drugs and schemes of treatment. The use of combination therapy has gained much attention in recent years as a possible strategy for overcoming the various shortcomings in the present arsenal. We recently described the effectiveness of tamoxifen in murine models of leishmaniasis, and here, we investigated the interactions between tamoxifen and amphotericin B, one of the most potent drugs used in leishmaniasis treatment. The in vitro interactions were indifferent for the association of tamoxifen and amphotericin B. The association was also assayed in vivo in Leishmania amazonensis-infected BALB/c mice and was found to yield at least additive effects at low doses of both drugs. PMID:24550333

  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. Synthesis, biodistribution, and estrogen receptor scintigraphy of indium-111-diethylenetriaminepentaacetic acid-tamoxifen analogue.

    PubMed

    Delpassand, E S; Yang, D J; Wallace, S; Cherif, A; Quadri, S M; Price, J; Joubert, A; Inoue, T; Podoloff, D A

    1996-06-01

    This study was aimed at developing a hydrophilic diethylenetriaminepentaacetic acid-tamoxifen (DTPA-Tam) analogue for use in imaging estrogen receptor positive (ER+) lesions. In rat uterine cytosol, the IC50 of DTPA-Tam conjugate was 1 microM and of tamoxifen, 2 microM. Biodistribution, autoradiography, and radionuclide imaging of 111In-DTPA-Tam in breast-tumor-bearing rats showed that tumor-to-tissue ratios increased steadily between 30 min and 48 h. The in vivo response of MCF-7 breast cancer xenografts to tamoxifen and DTPA-Tam in nude mice demonstrated that DTPA-Tam could reduce tumor growth rate. These results indicate that DTPA-Tam, a new hydrophilic ER+ ligand, might be useful in diagnosing ER+ lesions. PMID:8773948

  6. Simulation with cells in vitro of tamoxifen treatment in premenopausal breast cancer patients with different CYP2D6 genotypes

    PubMed Central

    Maximov, Philipp Y; McDaniel, Russell E; Fernandes, Daphne J; Korostyshevskiy, Valeriy R; Bhatta, Puspanjali; Mürdter, Thomas E; Flockhart, David A; Jordan, V Craig

    2014-01-01

    Background and Purpose Tamoxifen is a prodrug that is metabolically activated by 4-hydroxylation to the potent primary metabolite 4-hydroxytamoxifen (4OHT) or via another primary metabolite N-desmethyltamoxifen (NDMTAM) to a biologically active secondary metabolite endoxifen through a cytochrome P450 2D6 variant system (CYP2D6). To elucidate the mechanism of action of tamoxifen and the importance of endoxifen for its effect, we determined the anti-oestrogenic efficacy of tamoxifen and its metabolites, including endoxifen, at concentrations corresponding to serum levels measured in breast cancer patients with various CYP2D6 genotypes (simulating tamoxifen treatment). Experimental Approach The biological effects of tamoxifen and its metabolites on cell growth and oestrogen-responsive gene modulation were evaluated in a panel of oestrogen receptor-positive breast cancer cell lines. Actual clinical levels of tamoxifen metabolites in breast cancer patients were used in vitro along with actual levels of oestrogens observed in premenopausal patients taking tamoxifen. Key Results Tamoxifen and its primary metabolites (4OHT and NDMTAM) only partially inhibited the stimulant effects of oestrogen on cells. The addition of endoxifen at concentrations corresponding to different CYP2D6 genotypes was found to enhance the anti-oestrogenic effect of tamoxifen and its metabolites with an efficacy that correlated with the concentration of endoxifen; at concentrations corresponding to the extensive metabolizer genotype it further inhibited the actions of oestrogen. In contrast, lower concentrations of endoxifen (intermediate and poor metabolizers) had little or no anti-oestrogenic effects. Conclusions and Implications Endoxifen may be a clinically relevant metabolite in premenopausal patients as it provides additional anti-oestrogenic actions during tamoxifen treatment. PMID:25073551

  7. 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.

  8. Duration of tamoxifen use and the risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers.

    PubMed

    Gronwald, Jacek; Robidoux, Andre; Kim-Sing, Charmaine; Tung, Nadine; Lynch, Henry T; Foulkes, William D; Manoukian, Siranoush; Ainsworth, Peter; Neuhausen, Susan L; Demsky, Rochelle; Eisen, Andrea; Singer, Christian F; Saal, Howard; Senter, Leigha; Eng, Charis; Weitzel, Jeffrey; Moller, Pal; Gilchrist, Dawna M; Olopade, Olufunmilayo; Ginsburg, Ophira; Sun, Ping; Huzarski, Tomasz; Lubinski, Jan; Narod, Steven A

    2014-07-01

    Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20-0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1-4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44-1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment. PMID:24951267

  9. Prolonged tamoxifen exposure selects a breast cancer cell clone that is stable in vitro and in vivo.

    PubMed

    Sipila, P E; Wiebe, V J; Hubbard, G B; Koester, S K; Emshoff, V D; Maenpaa, J U; Wurz, G T; Seymour, R C; DeGregorio, M W

    1993-01-01

    The effects of long-term tamoxifen exposure on cell growth and cell cycle kinetics were compared between oestrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. In the MCF-7 cell line, prolonged tamoxifen exposure (0.5 mumol/l for > 100 days) blocked cells in G0-G1 of the cell cycle, and slowed the doubling time of cells from 30 to 59 h. These effects corresponded to an increase in the cellular accumulation of tamoxifen over time [mean area under concentration curve (AUC) = 77.92 mumoles/10(6)/cells/day]. In contrast, in the MDA-MB-231 cell line, long-term tamoxifen exposure had no obvious effect on the doubling time, and reduced cellular tamoxifen accumulation (mean AUC = 50.50 mumoles/10(6)/cells/day) compared to the MCF-7 cells. Flow cytometric analysis of MDA-MB-231 cells demonstrated that a new tetraploid clone emerged following 56 days of tamoxifen exposure. Inoculation of the MDA-MB-231 tetraploid clone and MDA-MB-231 wildtype cells into the opposite flanks of athymic nude mice resulted in the rapid growth of tetraploid tumours. The tetraploid tumours maintained their ploidy following tamoxifen treatment for nine consecutive serial transplantations. Histological examination of the fifth transplant generation xenografts revealed that the tetraploid tumour had a 25-30 times greater mass, area of haemorrhage and necrosis, a slightly higher mitotic index and was more anaplastic than the control neoplasm. The control wildtype MDA-MB-231 tumours maintained a stable ploidy following tamoxifen treatment until the eighth and ninth transplantation, when a tetraploid population appeared, suggesting that tamoxifen treatment may select for this clone in vivo. These studies suggest that prolonged tamoxifen exposure may select for new, stable, fast growing cell clones in vitro as well as in vivo. PMID:8297653

  10. Endoxifen, the active metabolite of tamoxifen, inhibits cloned hERG potassium channels.

    PubMed

    Chae, Yun Ju; Lee, Keon Jin; Lee, Hong Joon; Sung, Ki-Wug; Choi, Jin-Sung; Lee, Eun Hui; Hahn, Sang June

    2015-04-01

    The effects of tamoxifen, and its active metabolite endoxifen (4-hydroxy-N-desmethyl-tamoxifen), on hERG currents stably expressed in HEK cells were investigated using the whole-cell patch-clamp technique and an immunoblot assay. Tamoxifen and endoxifen inhibited hERG tail currents at -50mV in a concentration-dependent manner with IC50 values of 1.2 and 1.6μM, respectively. The steady-state activation curve of the hERG currents was shifted to the hyperpolarizing direction in the presence of endoxifen. The voltage-dependent inhibition of hERG currents by endoxifen increased steeply in the voltage range of channel activation. The inhibition by endoxifen displayed a shallow voltage dependence (δ=0.18) in the full activation voltage range. A fast application of endoxifen induced a reversible block of hERG tail currents during repolarization in a concentration-dependent manner, which suggested an interaction with the open state of the channel. Endoxifen also decreased the hERG current elicited by a 5s depolarizing pulse to +60mV to inactivate the hERG currents, suggesting an interaction with the activated (open and/or inactivated) states of the channels. Tamoxifen and endoxifen inhibited the hERG channel protein trafficking to the plasma membrane in a concentration-dependent manner with endoxifen being more potent than tamoxifen. These results indicated that tamoxifen and endoxifen inhibited the hERG current by direct channel blockage and by the disruption of channel trafficking to the plasma membrane in a concentration-dependent manner. A therapeutic concentration of endoxifen inhibited the hERG current by preferentially interacting with the activated (open and/or inactivated) states of the channel. PMID:25680947

  11. Neonatal tamoxifen treatment of mice leads to adenomyosis but not uterine cancer.

    PubMed

    Green, Andrew R; Styles, Jerry A; Parrott, Emma L; Gray, Douglas; Edwards, Richard E; Smith, Andrew G; Gant, Timothy W; Greaves, Peter; Al-Azzawi, Farook; White, Ian N H

    2005-03-01

    Tamoxifen is contraindicated during pregnancy but many births have been reported in breast cancer patients taking this drug and numbers might be expected to increase with FDA approval of tamoxifen for risk reduction in women at high, risk of breast cancer. The neonatal mouse, exquisitely sensitive to xenobiotic estrogens, has been used to investigate the effects of short-term oral dosing with tamoxifen (1 mg/kg on days 2-5 after birth) on long-term changes in uterine pathology and gene expression. Increased adenomyosis incidence and severity was evident in the tamoxifen-treated mice with increasing age. Uterine weights in treated mice remained lower than the corresponding controls up until 9 months, after which they became greater but during life-time studies (up to 36 months), there was no development of uterine tumours. Pathological examination of uterine tissues showed there to be extensive down-growth of endometrial glands and stroma into thickened, abnormal myometrium that had disorganised fascicles of smooth muscle and increased interstitial collagen deposition. In advanced cases, the endometrial epithelium showed mild degrees of focal hyperplasia and squamous metaplasia but no atypical cytology suggestive of premalignant change. Microarray analysis of uterine RNA taken at 1.5, 3, 6, 9 and 12 months showed from 4500 ESTs, only 12 genes were continuously over-expressed by tamoxifen treatment over this time, while none was continuously down-regulated. Up-regulated genes include those for nerve growth factor (Ngfa), cathepsin B (Ctsb), transforming growth factor beta induced (Tqfbi) and collagens (Colla1, Colla2). Results provide a basis for understanding the mechanism for tamoxifen induced tissue remodelling and the development of adenomyosis. PMID:15816354

  12. 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

  13. 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

  14. 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. PMID:25711483

  15. Efficacy of combined pharmacotherapy and psychotherapy versus monotherapy in the treatment of anxiety disorders.

    PubMed

    Black, Donald W

    2006-10-01

    Anxiety disorders in the United States are prevalent, widespread, and disabling. These illnesses may account for almost one third of the $148 billion total mental health bill each year. Pharmacologic options include tricyclic antidepressants, monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, and anxiolytics. Psychological treatments include cognitive-behavioral therapy (CBT), cognitive therapy, exposure, and ritual prevention therapies. Despite insufficient evidence, many experts recommend combined treatment, generally medication with CBT. A literature review was conducted to examine studies with random assignment, adequate methods and sample sizes, blind assessments, sufficient dosages and durations of treatment, and satisfactory reporting of data, to determine whether combined treatment was superior to monotherapy. Twenty-six randomized clinical trials were identified; nine met review criteria. A review of relevant studies could not confirm the superiority of combined treatment over monotherapy. In one of four studies of obsessive-compulsive disorder, combined treatment produced better results than monotherapy. There was no evidence of superiority for combined therapy over monotherapy for the treatment of social phobia or generalized anxiety disorder. There were no studies that met review criteria for either specific phobia or posttraumatic stress disorder (PTSD). With panic disorder, there was evidence that combined treatment might actually lead to worse outcome. Combined treatment is commonly recommended, but empirical support is limited. More research is needed. There are few well-designed studies, and little data regarding PTSD and specific phobias. PMID:17008828

  16. Mitochondria: the gateway for tamoxifen-induced liver injury.

    PubMed

    Ribeiro, Mariana P C; Santos, Armanda E; Custódio, José B A

    2014-09-01

    Tamoxifen (TAM) is routinely used in the treatment of breast carcinoma. TAM-induced liver injury remains a major concern, as TAM causes hepatic steatosis in a significant number of patients, which can progress toward steatohepatitis. Liver toxicity is generally believed to involve mitochondrial dysfunction and TAM exerts multiple deleterious effects on mitochondria, which may account for the hepatotoxicity observed in patients treated with TAM. Endoxifen (EDX), a key active metabolite of TAM that is being investigated as an alternative to TAM in breast cancer therapy, slightly affects mitochondria in comparison with TAM and this demonstration well correlates with the absence of alterations in the clinical parameters of individuals taking EDX. The steady-state plasma concentrations of TAM and its active metabolites EDX and 4-hydroxytamoxifen (OHTAM) in patients taking TAM are highly variable, reflecting genetic variants of CYP2D6 involved in TAM metabolism. Besides de genetic polymorphisms, the intake of drugs that influence the enzymatic activity of CYP2D6 compromises the therapeutic efficiency of TAM. The knowledge of the impact of the variability of TAM metabolism in the breast cancer treatment explains the discrepant outcomes observed in patients taking TAM, as well as the individual variability of idiosyncratic liver injury and other sides effects observed. Therefore, and contrarily to the clinical use of EDX, the need of therapeutic drug monitoring and a regular assessment of liver function biomarkers should be considered in patients under therapies with TAM. In this review we focus on the mitochondrial effects of TAM and its metabolites and on the role played by mitochondria in the initiating events leading to TAM-induced hepatotoxicity, as well as the clinical implications. PMID:24881593

  17. Adjuvant Therapy with High-Dose Medroxyprogesterone Acetate for Operable Breast Cancer.

    PubMed

    Koyama

    1999-04-25

    BACKGROUND: Medroxyprogesterone acetate (MPA) produces a comparable or higherresponse rate in metastatic breast cancer compared with tamoxifen which is alsocommonly used for adjuvant endocrine therapy. Several studies in the West have indicated the efficacy of MPA when used as an adjuvant to surgery in certain subsets of patients. The present study was undertaken as a multicenter open study in Japan to investigate the safety and efficacy of MPA in adjuvant endocrine therapy. Method and Patients: A combination of 800 mg/day MPA and a fluorouracil compound for 6 months was given postoperatively to 119 patients with stage II or IIIabreast cancer in 32 participating hospitals between June 1987 and June 1989. RESULTS: Among the 119 patients, 59 patients (49.6%) experienced some kind ofadverse reaction. The major adverse reaction was abnormal menstruation, seen in 13 (25.0%) of the 52 premenopausal patients. Vaginal bleeding was a major adverse reaction in the 67 postmenopausal patients (8/67 or 11.9%). An increase in body weight and moon face were observed in 23 (19.3%) and 9 (7.6%) of the 119 patients, respectively. Administration of drugs was discontinued because of adversereaction in 17 patients (14.3%), and dose reduction or temporary suspension wasnecessary in 7 patients (5.9%). Increase in body weight was the main reason fordiscontinuation of the treatment. No severe adverse reactions were observed. After a median follow-up of 74.5 months (range, 2.2-90.0 months), 84 of the 119 patients are alive with no evidence of disease. The 3-year and 5-year disease-freesurvival rates were 88.2% and 82.6% in stage II patients, and 64.7% and 52.9% in stage IIIa patients, respectively. The 3-year and 5-year disease-free survivalrates according to age were 87.8% and 79.3% in patients aged 50 years or more, and 78.6% and 71.4% in patients aged under 50 years. CONCLUSION: These results show that 800 mg/day MPA plus a fluorouracil compound can be administered with acceptable

  18. 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.

  19. 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.

  20. [Rectal cancer and adjuvant chemotherapy: which conclusions?].

    PubMed

    Bachet, J-B; Rougier, P; de Gramont, A; André, T

    2010-01-01

    Adenocarcinoma of the rectum represents about a third of cases of colorectal cancer, with an annual incidence of 12,000 cases in France. On the contrary of colon cancer, the benefice of adjuvant chemotherapy in rectal cancer has not been definitively proved, more because this question was assessed in few recent studies than because negative results. Preoperative radiochemotherapy is now the reference treatment for mid and lower rectal cancers, and allow to increase the local control without improvement of progression free survival and overall survival. The data of the "historical studies" of adjuvant treatment in rectal cancer published before 1990, of the meta-analysis of adjuvant trials in rectal cancer and of the QUASAR study suggest that adjuvant chemotherapy with fluoropyrimidines (intravenous or oral), in absence of pre-operative treatment, decrease the risk of metastatic relapse after curative surgery for a rectal cancer of stage II or III. This benefice seems similar to the one observed in colon cancer. In the EORTC radiotherapy group trial 22921, an adjuvant chemotherapy with 5-fluorouracil and low dose of leucovorin was not associated with a significantly improvement of overall survival but, despite the fact that only 42.9% of patients received all planed cycles, the progression free survival was increased (not significantly) in groups receiving adjuvant chemotherapy. The French recommendations are to discuss the indication of adjuvant chemotherapy by fluoropyrimidines in cases of stage III rectal cancer on histopathologic reports and no chemotherapy in case of stade II. Despite the fact that none study have assessed a combination of fluoropyrimidines and oxaliplatin in adjuvant setting in rectal cancer, like in colon cancer, the Folfox4, modified Folfox6 or Xelox regimens are valid options in stage III (experts opinion). In cases of pathologic complete remission or in absence of involved nodes, the benefice of adjuvant chemotherapy is not assessed. In

  1. 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

  2. Adherence to adjuvant endocrine therapy in estrogen receptor–positive breast cancer patients with regular follow-up

    PubMed Central

    Simon, Renée; Latreille, Jean; Matte, Claire; Desjardins, Pierre; Bergeron, Eric

    2014-01-01

    Background Adjuvant hormonal therapy is crucial in the treatment of estrogen receptor–positive breast cancer. The nonadherence rate to hormonal treatment is reported to be as high as 60%. The goal of this study was to evaluate the factors evoked by the patients as well as the demographic and disease-related factors that could be associated with nonadherence to adjuvant hormonal therapy. Methods All consecutive patients treated for an estrogen receptor–positive breast cancer who showed up for regular follow-up with a single breast specialist between November 2008 and April 2009 were included in the study. We assessed adherence to hormonal therapy (either with tamoxifen or aromatase inhibitor). Reasons for adherence and nonadherence were collected. Records were also reviewed for demographic and cancer characteristics and for treatment components. Results We included 161 patients in the study; 150 (93.2%) adhered to hormonal treatment. Side effects and absence of conviction were the main reasons for nonadherence. The importance of the diagnosis of cancer, fear of recurrence and regular follow-up were reported as the main reasons for adherence. Conclusion Severity of disease and side effects are associated with nonadherence to treatment. Strict follow-up appears to be a necessary adjunct in the adherence to treatment. The association between demographic and cancer characteristics and treatment components needs further investigation. However, these factors may help identify patients at risk of nonadherence and help the oncology team. PMID:24461223

  3. 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

  4. Pharmacological influence on processes of adjuvant arthritis: Effect of the combination of an antioxidant active substance with methotrexate.

    PubMed

    Drafi, Frantisek; Bauerova, Katarina; Kuncirova, Viera; Ponist, Silvester; Mihalova, Danica; Fedorova, Tatiana; Harmatha, Juraj; Nosal, Radomir

    2012-06-01

    Oxygen metabolism has an important role in the pathogenesis of rheumatoid arthritis. A certain correlation was observed between oxidative stress, arthritis and the immune system. Reactive oxygen species produced in the course of cellular oxidative phosphorylation and by activated phagocytic cells during oxidative burst, exceed the physiological buffering capacity and result in oxidative stress. The excessive production of ROS can damage protein, lipids, nucleic acids, and matrix components. Patients with rheumatoid arthritis have an altered antioxidant defense capacity barrier. In the present study the effect of substances with antioxidative properties, i.e. pinosylvin and carnosine, was determined in monotherapy for the treatment of adjuvant arthritis (AA). Moreover carnosine was evaluated in combination therapy with methotrexate. Rats with AA were administered first pinosylvin (30 mg/kg body mass daily per os), second carnosine (150 mg/kg body mass daily per os) in monotherapy for a period of 28 days. Further, rats with AA were administered methotrexate (0.3 mg/kg body mass 2-times weekly per os), and a combination of methotrexate+carnosine, with the carnosine dose being the same as in the previous experiment. Parameters, i.e. changes in hind paw volume and arthritic score were determined in rats as indicators of destructive arthritis-associated clinical changes. Plasmatic levels of TBARS and lag time of Fe(2+)-induced lipid peroxidation (tau-FeLP) in plasma and brain were specified as markers of oxidation. Plasmatic level of CRP and activity of γ-glutamyltransferase (GGT) in spleen and joint were used as inflammation markers. In comparison to pinosylvin, administration of carnosine monotherapy led to a significant decrease in the majority of the parameters studied. In the combination treatment with methotrexate+carnosine most parameters monitored were improved more remarkably than by methotrexate alone. Carnosine can increase the disease-modifying effect of

  5. Rethinking tamoxifen in the management of melanoma: New answers for an old question.

    PubMed

    Ribeiro, Mariana P C; Santos, Armanda E; Custódio, José B A

    2015-10-01

    The use of the antiestrogen tamoxifen in melanoma therapy is controversial due to the unsuccessful outcomes and a still rather unclarified mechanism of action. It seemed that the days of tamoxifen in malignant melanoma therapy were close to an end, but new evidence may challenge this fate. On one hand, it is now believed that metabolism is a major determinant of tamoxifen clinical outcomes in breast cancer patients, which is a variable that has yet to be tested in melanoma patients, since the tamoxifen active metabolite endoxifen demonstrated superior cytostatic activity over the parent drug in melanoma cells; on the other hand, new evidence has emerged regarding estrogen-mediated signaling in melanoma cells, including the methylation of the estrogen receptor-α gene promoter and the expression of the G protein coupled estrogen receptor. The expression of estrogen receptor-α and G protein coupled estrogen receptor, as well as the cytochrome P450 (CYP) 2D6 genotype, may be used as predictive biomarkers to select the patients that may respond to antiestrogens based on specific traits of their tumors. This review focused on these new evidences and how they may contribute to shed new light on this long-lasting controversy, as well as their possible implications for future investigations. PMID:26165763

  6. Characterization of parameters required for effective use of tamoxifen-regulated recombination.

    PubMed

    Buelow, Ben; Scharenberg, Andrew M

    2008-01-01

    Conditional gene targeting using the Cre-loxp system is a well established technique in numerous in vitro and in vivo systems. Ligand regulated forms of Cre have been increasingly used in these applications in order to gain temporal and spatial control over conditional targeting. The tamoxifen-regulated Cre variant mer-Cre-mer (mCrem) is widely utilized because of its reputation for tight regulation in the absence of its tamoxifen ligand. In the DT40 chicken B cell line, we generated an mCrem-based reversible switch for conditional regulation of a transgene, and in contrast with previous work, observed significant constitutive activity of mCrem. This prompted us to use our system for analysis of the parameters governing tamoxifen-regulated mCrem recombination of a genomic target. We find that robust mCrem expression correlates with a high level of tamoxifen-independent Cre activity, while clones expressing mCrem at the limit of western blot detection exhibit extremely tight regulation. We also observe time and dose-dependent effects on mCrem activity which suggest limitations on the use of conditional targeting approaches for applications which require tight temporal coordination of Cre action within a cell population. PMID:18810268

  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. 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. |

  9. Dietary Fat, Tamoxifen Use and Circulating Sex Hormones in Postmenopausal Breast Cancer Survivors

    PubMed Central

    Neuhouser, Marian L.; Nojomi, Marzieh; Baumgartner, Richard N.; Baumgartner, Kathy B.; Gilliland, Frank; Bernstein, Leslie; Stanczyk, Frank; Ballard-Barbash, Rachel; McTiernan, Anne

    2013-01-01

    Evidence is inconsistent regarding whether dietary fat influences sex hormone concentrations. This issue is important for breast cancer survivors since clinical recommendations suggest maintaining low hormone levels primarily via pharmacologic agents. This study examines associations between dietary fat and circulating sex hormones among participants in the HEAL (Health, Eating, Activity and Lifestyle) Study, a cohort of breast cancer survivors (n=511). During a post-diagnosis interview, detailed data were collected on diet, physical activity, lifestyle habits, and medication use (including tamoxifen). Staff measured height and weight and collected fasting bloods. Multivariate linear regression modeled associations of dietary fat with serum sex hormones. Among women using tamoxifen, we observed modest inverse associations of dietary fat with estrone (p< 0.01), estradiol (p< 0.05), testosterone (p< 0.01), free testosterone (p< 0.01), and DHEA (p< 0.01) for higher vs. lower fat intake, but there was no evidence for a trend. Associations were consistent across measures (percent energy from fat, total, saturated and polyunsaturated fat) and modest effect modification was observed between fat intake and tamoxifen in relation to hormones. Among women not using tamoxifen, fat intake was not associated with hormone concentrations. Further work is needed to confirm the findings and to understand the clinical implications of these observations. PMID:20099190

  10. Phase II trial of cyclophosphamide, leucovorin, 5-fluorouracil 24-hour infusion and tamoxifen in pancreatic cancer.

    PubMed

    Eckel, F; Lersch, C; Lippl, F; Assmann, G; Schulte-Frohlinde, E

    2000-09-01

    Leucovorin modulates the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. 24-hour infusion of 5-FU has been shown to enhance antitumor activity in colorectal cancer compared to bolus infusion. According to experimental data cyclophosphamide and tamoxifen may enhance the effectiveness of leucovorin and 5-FU. A phase II trial was initiated to evaluate the effect of a combination of low-dose cyclophosphamide (C), leucovorin (L), 5-FU (F) and tamoxifen (T) (CLFT) in advanced pancreatic cancer. Fifty patients were treated monthly with 300 mg/m2 cyclophosphamide and weekly with 500 mg/m2 leucovorin followed by a 24-hour infusion of 2000 mg/m2 5-FU and tamoxifen 20 mg bid. Three patients had a partial response (6%), two a minor response (4%) and 32 (64%) no change of disease. The median survival time was 8.5 months for all patients, the median time to progression of disease was 4.6 months and the 1-year survival rate was 28%. CLFT was fairly well tolerated. These data suggest that biochemical modulation of 24-hour infusional 5-FU with leucovorin together with cyclophosphamide and tamoxifen has some positive effects in the treatment of pancreatic cancer. PMID:11144522

  11. Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells

    PubMed Central

    2010-01-01

    Introduction The HIV protease inhibitor nelfinavir is currently under investigation as a new anti-cancer drug. Several studies have shown that nelfinavir induces cell cycle arrest, endoplasmic reticulum stress, autophagy, and apoptosis in cancer cells. In the present article, the effect of nelfinavir on human breast cancer cells is examined and potential combination treatments are investigated. Methods The effects of nelfinavir and tamoxifen on the human breast cancer cell lines MCF7, T47 D, MDA-MB-453, and MDA-MB-435 were tested by analysing their influence on cell viability (via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay), apoptosis (annexin binding, poly(ADP-ribose) polymerase cleavage), autophagy (autophagy marker light chain 3B expression), endoplasmic reticulum stress (binding protein and activating transcription factor 3 expression), and the occurrence of oxidative stress (intracellular glutathione level). Results Nelfinavir induced apoptosis in all four breast cancer cell lines tested, although the extent of autophagy and endoplasmic reticulum stress varied among the cell lines. The concentration of nelfinavir needed for an efficient induction of apoptosis in breast cancer cells could be reduced from 15 μg/ml to 6 μg/ml when combined with tamoxifen. At a concentration of 6 μg/ml, tamoxifen substantially enhanced the endoplasmic reticulum stress reaction in those cell lines that responded to nelfinavir with binding protein (BiP) upregulation (MCF7, T47D), and enhanced autophagy in cell lines that responded to nelfinavir treatment with autophagy marker light chain 3B upregulation (MDA-MB-453). Although tamoxifen has been described to be able to induce oxidative stress at concentrations similar to those applied in this study (6 μg/ml), we observed that nelfinavir but not tamoxifen reduced the intracellular glutathione level of breast cancer cells within hours of application by up to 32%, suggesting the induction of oxidative stress

  12. Memantine Monotherapy for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

    PubMed Central

    Matsunaga, Shinji; Kishi, Taro; Iwata, Nakao

    2015-01-01

    Background We performed an updated meta-analysis of randomized placebo-controlled trials testing memantine monotherapy for patients with Alzheimer’s disease (AD). Methods The meta-analysis included randomized controlled trials of memantine monotherapy for AD, omitting those in which patients were also administered a cholinesterase inhibitor. Cognitive function, activities of daily living, behavioral disturbances, global function, stage of dementia, drug discontinuation rate, and individual side effects were compared between memantine monotherapy and placebo groups. The primary outcomes were cognitive function and behavioral disturbances; the others were secondary outcomes. Results Nine studies including 2433 patients that met the study’s inclusion criteria were identified. Memantine monotherapy significantly improved cognitive function [standardized mean difference (SMD)=−0.27, 95% confidence interval (CI)=−0.39 to −0.14, p=0.0001], behavioral disturbances (SMD=−0.12, 95% CI=−0.22 to −0.01, p=0.03), activities of daily living (SMD=−0.09, 95% CI=−0.19 to −0.00, p=0.05), global function assessment (SMD=−0.18, 95% CI=−0.27 to −0.09, p=0.0001), and stage of dementia (SMD=−0.23, 95% CI=−0.33 to −0.12, p=0.0001) scores. Memantine was superior to placebo in terms of discontinuation because of inefficacy [risk ratio (RR)=0.36, 95% CI=0.17¬ to 0.74, p=0.006, number needed to harm (NNH)=non significant]. Moreover, memantine was associated with less agitation compared with placebo (RR=0.68, 95% CI=0.49 to 0.94, p=0.02, NNH=non significant). There were no significant differences in the rate of discontinuation because of all causes, all adverse events, and individual side effects other than agitation between the memantine monotherapy and placebo groups. Conclusions Memantine monotherapy improved cognition, behavior, activities of daily living, global function, and stage of dementia and was well-tolerated by AD patients. However, the effect

  13. FFCD-1004 Clinical Trial: Impact of Cytidine Deaminase Activity on Clinical Outcome in Gemcitabine-Monotherapy Treated Patients

    PubMed Central

    Serdjebi, Cindy; Gagnière, Johan; Desramé, Jérôme; Fein, Francine; Guimbaud, Rosine; François, Eric; André, Thierry; Seitz, Jean-François; Montérymard, Carole; Arsene, Dominique; Volet, Julien; Abakar-Mahamat, Abakar; Lecomte, Thierry; Guerin-Meyer, Véronique; Legoux, Jean-Louis; Deplanque, Gaël; Guillet, Pierre; Ciccolini, Joseph; Lepage, Côme; Dahan, Laetitia

    2015-01-01

    Purpose Because cytidine deaminase (CDA) is the key enzyme in gemcitabine metabolism, numerous studies have attempted to investigate impact of CDA status (i.e. genotype or phenotype) on clinical outcome. To date, data are still controversial because none of these studies has fully investigated genotype-phenotype CDA status, pharmacokinetics and clinical outcome relationships in gemcitabine-treated patients. Besides, most patients were treated with gemcitabine associated with other drugs, thus adding a confounding factor. We performed a multicenter prospective clinical trial in gemcitabine-treated patients which aimed at investigating the link between CDA deficiency on the occurrence of severe toxicities and on pharmacokinetics, and studying CDA genotype-phenotype relationships. Experimental design One hundred twenty patients with resected pancreatic adenocarcinoma eligible for adjuvant gemcitabine monotherapy were enrolled in this study promoted and managed by the Fédération Francophone de Cancérologie Digestive. Toxicities were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events Version 4. They were considered severe for grade ≥ 3, and early when occurring during the first eight weeks of treatment. CDA status was evaluated using a double approach: genotyping for 79A>C and functional testing. Therapeutic drug monitoring of gemcitabine and its metabolite were performed on the first course of gemcitabine. Results Five patients out of 120 (i.e., 4.6%) were found to be CDA deficient (i.e., CDA activity <1.3 U/mg), and only one among them experienced early severe hematological toxicity. There was no statistically significant difference in CDA activity between patients experiencing hematological severe toxicities (28.44%) and patients who tolerated the treatment (71.56%). CDA genetic analysis failed in evidencing an impact in terms of toxicities or in CDA activity. Regarding pharmacokinetics, a wide inter

  14. 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

  15. Feasibility and early outcome of high-dose-rate Ir-192 brachytherapy as monotherapy in two fractions within 1 day for high-/very high-risk prostate cancer

    PubMed Central

    ASHIDA, SHINGO; YAMASAKI, ICHIRO; TAMURA, KENJI; SHIMAMOTO, TSUTOMU; INOUE, KEIJI; KARIYA, SHINJI; KOBAYASHI, KANA; YAMAGAMI, TAKUJI; SHUIN, TARO

    2016-01-01

    The aim of the present study was to evaluate the feasibility and preliminary outcomes of high-dose-rate (HDR)-brachytherapy as a monotherapy in two fractions within 1 day for localized prostate cancer, including high-/very high-risk cases. Among the 68 patients treated with HDR monotherapy between July 2011 and December 2014, 65 had a minimal follow-up of 12 months without adjuvant androgen deprivation therapy and were enrolled in the present study [42/65 (64.6%) exhibited high-/very high-risk diseases]. HDR monotherapy was performed in two fractions with a minimal interval of 6 h and the prescribed dose was 13.5 Gy (×2). Adverse events (AEs) were assessed using Common Terminology Criteria for Adverse Events (version 4; http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40), and biochemical failure was assessed by the Phoenix definition. The median follow-up time was 30.1 months. The majority of patients had Grade 0–1 acute AEs. Four patients (6.2%) exhibited urinary retention, requiring a Foley catheter. Grade 3 acute AEs occurred at a frequency of 3.1% and hematuria at 1.5%. The majority of patients also exhibited Grade 0–1 chronic AEs. Grade 3 chronic AEs occurred at a frequency of 1.5% and urethral stricture at 1.5%, for which endoscopic treatment was indicated. Acute and chronic gastrointestinal AEs were uncommon, and no Grade 3 or above AEs developed. Biochemical failure occurred in 4 patients who all exhibited high-/very high-risk diseases. Kaplan-Meier estimated that 3 year biochemical failure-free survival was 91.6% overall and 88.0% in high-/very high-risk cases. The present two-fraction 1 day HDR monotherapy is feasible with minimal AEs and achieved acceptable biochemical control of localized prostate cancer, including high-/very high-risk cases, although long-term follow-up is required. PMID:27123280

  16. Weight gain during adjuvant endocrine treatment for early-stage breast cancer: What is the evidence?

    PubMed

    Nyrop, K A; Williams, G R; Muss, H B; Shachar, S S

    2016-07-01

    Most breast cancer (BC) tumors are early stage and hormone receptor positive, where treatment generally includes adjuvant endocrine treatment (ET). Oncology providers and women about to start ET want to know about side effects, including potential weight gain. The aim of this study was a literature review to identify the independent effect of ET on post-diagnosis weight gain. Weight gain is of concern with regard to potential associations with BC recurrence, mortality, and quality of life in survivorship. We conducted a targeted review of the literature. Thirty-eight studies met our inclusion criteria. Patient-reported weight gain ranged widely from 18 to 52 % of patients in Year 1 and from 7 to 55 % in Year 5. Some studies reported categories of weight change: lost weight (9-17 %), stable weight (47-64 %), and gained weight (27-36 %). Most studies comparing ET with placebo or tamoxifen with AI reported no significant difference between the two groups. Wide-ranging and inconsistent results point to the need for further research to clarify annual weight change (loss, gain, stability) from BC diagnosis through 5 years of ET and beyond. There is also a need to explore weight change by type of ET and to explore risk factors for weight gain in women on ET, including tumor type, sociodemographic characteristics, and health behaviors. More specific information is needed to identify high-risk BC patients who could be targeted for weight management interventions. PMID:27342454

  17. 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.

  18. 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

  19. 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

  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. Pregnancy outcomes in patients with severe pulmonary hypertension and Eisenmenger syndrome treated with sildenafil monotherapy

    PubMed Central

    Alan, Pichy Ann; Benedicto, Jubert

    2014-01-01

    Pregnancy outcomes in patients with pulmonary arterial hypertension have not been documented in our local setting. In our institution, access to therapies like nitric oxide, inhaled prostacyclin and iloprost is limited. We describe two such women given sildenafil monotherapy between April and May 2011. Both had an atrial septal defect complicated by Eisenmenger syndrome. Both survived – one after elective Caesarean section for malpresentation (breech) under general anaesthesia, the other after an assisted vaginal delivery. In addition to oral sildenafil, both received oxygen supplementation. To date, there have been three reported cases of pulmonary arterial hypertension in pregnancy treated with sildenafil in combination with another drug. Our two cases demonstrate that treatment for pulmonary arterial hypertension using sildenafil as monotherapy may allow stabilization of the maternal condition and improve clinical outcomes for both mother and baby. However, pregnancy is still discouraged in women with pulmonary arterial hypertension.

  2. A case of esophageal adenocarcinoma on long-term rapamycin monotherapy.

    PubMed

    Canha, Catarina; Ferreira, Raquel; Rovira, Jordi; Moya-Rull, Daniel; Castells, Antoni; Diekmann, Fritz; Oppenheimer, Federico; Campistol, Josep Maria; Revuelta, Ignacio

    2015-10-01

    Cancer in transplant recipients represents a therapeutic challenge even when the patient is already under mTOR inhibitors. A 78-year-old man received a deceased donor kidney transplant in 1993. After 6 months, he developed a multifocal cutaneous and nonvisceral Kaposi's Sarcoma while on cyclosporine immunosuppressant therapy. The patient was converted to sirolimus monotherapy in 2001 with subsequent complete recovery within 2 years. In 2007, the patient was diagnosed with an esophageal adenocarcinoma stage IIA. An esophagectomy was performed without requirement of further treatment. He has continued on sirolimus monotherapy ever since, with no other incidents and no recurrences of either tumor. In this report, we describe an interesting case of a second cancer while on immunosuppressive therapy with anticancer activity. Moreover, the present knowledge of the matter is discussed. PMID:25939687

  3. [Complete response in a case of anastomotic recurrence of rectal cancer treated with S-1 monotherapy].

    PubMed

    Kabashima, Akira; Kitagawa, Dai; Nakamura, Toshihiko; Kondo, Naoko; Teramoto, Seiichi; Saito, Genkichi; Funahashi, Tomoru; Adachi, Eisuke; Ikeda, Yoichi

    2014-11-01

    A 63-year-old woman underwent a low anterior resection for rectal cancer in 2002.A n anastomotic recurrence was diagnosed in July 2011.S he rejected the possibility of colostomy as radical surgery.Chemotherapy consisting of capecitabine+ oxaliplatin (XELOX) or folinic acid, fluorouracil, and oxaliplatin (FOLFOX6) + bevacizumab were not possible because of high costs. In view of the lower costs and the potential for ambulation, S-1 monotherapy was started. After 3 months, a reduction in the recurrent lesion was observed.After 19 months, the recurrent lesion revealed a scar, which was judged by biopsy to be Group 1.We had achieved a pathological complete response (CR).The standard treatment for recurrent colon cancer is surgical resection or multidrug chemotherapy. However, in view of a patient's quality of life (QOL), S-1 monotherapy may be considered as a potential therapy. PMID:25731306

  4. [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

  5. 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.

  6. 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. PMID:26928033

  7. Systemic adjuvant therapies in renal cell carcinoma.

    PubMed

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

    2012-10-01

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

  8. CpG DNA as mucosal adjuvant.

    PubMed

    McCluskie, M J; Davis, H L

    1999-09-01

    We have previously found synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs to be a potent adjuvant to protein administered by intramuscular injection or intranasal inhalation to BALB/c mice. Herein we have further evaluated the potential of CpG ODN as a mucosal adjuvant to purified hepatitis B surface antigen (HBsAg) when administered alone or with cholera toxin (CT). CpG ODN and CT both augmented systemic (humoral and cellular) and mucosal immune responses against HBsAg, and these could be further enhanced with higher doses of adjuvant or boosting. Overall, antibody isotypes with CT alone were predominantly IgG1 (Th2-like) whereas they were predominantly IgG2a (Th1-like) with CpG ODN alone or in combination with CT. Results from this study indicate that stimulatory CpG ODN are promising new adjuvants for mucosal vaccination strategies, whether used alone or in combination with other mucosal adjuvants. PMID:10506647

  9. Parameters of metabolic syndrome in Indian children with epilepsy on valproate or phenytoin monotherapy

    PubMed Central

    Dhir, Aditi; Sharma, Suvasini; Jain, Puneet; Bhakhri, Bhanu K.; Aneja, Satinder

    2015-01-01

    Objectives: The prevalence of obesity is rapidly increasing among Indian children, who, in general, are more prone to develop metabolic complications at an early age. Valproate and phenytoin are commonly used antiepileptic drugs in children. This study aimed to assess the parameters of the metabolic syndrome in Indian children with epilepsy on valproate or phenytoin monotherapy. Methods: This cross-sectional study recruited children from the Pediatric Epilepsy Clinic, Department of Pediatrics, Kalawati Saran Children Hospital, New Delhi from March 2012 to September 2012. All consecutive children diagnosed with epilepsy as per International League Against Epilepsy definition aged 3–18 years on valproate or phenytoin monotherapy for at least 6 months were enrolled at a tertiary care children's hospital in Northern India. After clinical and anthropometric evaluation (including body mass index [BMI] and waist circumference), the blood samples were analyzed for fasting serum glucose, total cholesterol, high-density lipoprotein-cholesterol, and serum triglyceride. Results: Children with BMI >95th centile and waist circumference >90th centile were not significantly different among children on valproate and phenytoin monotherapy. Children on valproate had significantly higher mean serum triglyceride (96.9 mg/dL vs. 77.6 mg/dL; P < 0.001) and total cholesterol (148.3 mg/dL vs. 132.8 mg/dL; P = 0.002) levels as compared to children on phenytoin monotherapy. Conclusions: The lipid abnormalities may be observed in children on valproate or phenytoin therapy and may warrant periodic screening. PMID:26557161

  10. High-Dose-Rate Monotherapy: Safe and Effective Brachytherapy for Patients With Localized Prostate Cancer

    SciTech Connect

    Demanes, D. Jeffrey; Martinez, Alvaro A.; Ghilezan, Michel; Hill, Dennis R.; Schour, Lionel; Brandt, David; Gustafson, Gary

    2011-12-01

    Purpose: High-dose-rate (HDR) brachytherapy used as the only treatment (monotherapy) for early prostate cancer is consistent with current concepts in prostate radiobiology, and the dose is reliably delivered in a prospectively defined anatomic distribution that meets all the requirements for safe and effective therapy. We report the disease control and toxicity of HDR monotherapy from California Endocurietherapy (CET) and William Beaumont Hospital (WBH) in low- and intermediate-risk prostate cancer patients. Methods and Materials: There were 298 patients with localized prostate cancer treated with HDR monotherapy between 1996 and 2005. Two biologically equivalent hypofractionation protocols were used. At CET the dose was 42 Gy in six fractions (two implantations 1 week apart) delivered to a computed tomography-defined planning treatment volume. At WBH the dose was 38 Gy in four fractions (one implantation) based on intraoperative transrectal ultrasound real-time treatment planning. The bladder, urethral, and rectal dose constraints were similar. Toxicity was scored with the National Cancer Institute Common Toxicity Criteria for Adverse Events version 3. Results: The median follow-up time was 5.2 years. The median age of the patients was 63 years, and the median value of the pretreatment prostate-specific antigen was 6.0 ng/mL. The 8-year results were 99% local control, 97% biochemical control (nadir +2), 99% distant metastasis-free survival, 99% cause-specific survival, and 95% overall survival. Toxicity was scored per event, meaning that an individual patient with more than one symptom was represented repeatedly in the morbidity data table. Genitourinary toxicity consisted of 10% transient Grade 2 urinary frequency or urgency and 3% Grade 3 episode of urinary retention. Gastrointestinal toxicity was <1%. Conclusions: High disease control rates and low morbidity demonstrate that HDR monotherapy is safe and effective for patients with localized prostate cancer.

  11. Amrubicin Monotherapy for Patients with Platinum-Refractory Gastroenteropancreatic Neuroendocrine Carcinoma.

    PubMed

    Ando, Takayuki; Hosokawa, Ayumu; Yoshita, Hiroki; Ueda, Akira; Kajiura, Shinya; Mihara, Hiroshi; Nanjo, Sohachi; Fujinami, Haruka; Nishikawa, Jun; Ogawa, Kohei; Nakajima, Takahiko; Imura, Johji; Sugiyama, Toshiro

    2015-01-01

    Objective. Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor prognosis. Platinum-based combination chemotherapy is commonly used as first-line treatment; however, the role of salvage chemotherapy remains unknown. This study aimed to analyze the efficacy and safety of amrubicin monotherapy in patients with platinum-refractory gastroenteropancreatic NEC. Methods. Among 22 patients with advanced gastroenteropancreatic NEC, 10 received amrubicin monotherapy between September 2007 and May 2014 after failure of platinum-based chemotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively. Results. Eight males and two females (median age, 67 years (range, 52-78)) received platinum-based chemotherapy, including cisplatin plus irinotecan (n = 7, 70%), cisplatin plus etoposide (n = 2, 20%), and carboplatin plus etoposide (n = 1, 10%) before amrubicin therapy. Median progression-free survival and overall survival after amrubicin therapy were 2.6 and 5.0 months, respectively. Two patients had partial response (20% response rate), and their PFS were 6.2 months and 6.3 months, respectively. Furthermore, NEC with response for amrubicin had characteristics with a high Ki-67 index and receipt of prior chemotherapy with cisplatin and irinotecan. Grade 3-4 neutropenia and anemia were observed in four and five patients, respectively. Conclusion. Amrubicin monotherapy appears to be potentially active and well-tolerated for platinum-refractory gastroenteropancreatic NEC. PMID:26199623

  12. 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. PMID:22515652

  13. 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

  14. Adjuvant radiation for soft tissue sarcomas.

    PubMed

    Dickie, Colleen I; Haas, Rick; O'Sullivan, Brian

    2015-01-01

    Over recent decades, limb-preservation surgery in combination with radiotherapy achieves local control rates exceeding 90% for extremity soft tissue sarcoma (STS). Local control is not as successful for retroperitoneal sarcoma (approximately 60%) despite aggressive surgical approaches including en bloc resection of uninvolved adjacent organs combined with intensity modulated radiotherapy (IMRT). This review will discuss the indications for adjuvant radiation therapy (RT) for primary presentation of soft tissue sarcoma: "What," referring to the type and manner of planning and delivery of RT; "When," referring to the timing and scheduling of RT; and "Why," referring to the rationale for the use of RT will be addressed. From a practical stand point, this Educational Chapter on "adjuvant RT" will focus on pre- and postoperative RT in the context of gross total resection for extremity and retroperitoneal soft tissue sarcoma, the two most frequent paradigms for the use of adjuvant RT. PMID:25993234

  15. Systemic immunotoxicity reactions induced by adjuvanted vaccines.

    PubMed

    Batista-Duharte, Alexander; Portuondo, Deivys; Pérez, O; Carlos, Iracilda Zeppone

    2014-05-01

    Vaccine safety is a topic of concern for the treated individual, the family, the health care personnel, and the others involved in vaccination programs as recipients or providers. Adjuvants are necessary components to warrant the efficacy of vaccines, however the overstimulation of the immune system is also associated with adverse effects. Local reactions are the most frequent manifestation of toxicity induced by adjuvanted vaccines and, with the exception of the acute phase response (APR), much less is known about the systemic reactions that follow vaccination. Their low frequency or subclinical expression meant that this matter has been neglected. In this review, various systemic reactions associated with immune stimulation will be addressed, including: APR, hypersensitivity, induction or worsening of autoimmune diseases, modification of hepatic metabolism and vascular leak syndrome (VLS), with an emphasis on the mechanism involved. Finally, the authors analyze the current focus of discussion about vaccine safety and opportunities to improve the design of new adjuvanted vaccines in the future. PMID:24607449

  16. CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increases endoxifen serum concentrations without increasing side effects.

    PubMed

    Dezentjé, V O; Opdam, F L; Gelderblom, H; Hartigh den, J; Van der Straaten, T; Vree, R; Maartense, E; Smorenburg, C H; Putter, H; Dieudonné, A S; Neven, P; Van de Velde, C J H; Nortier, J W R; Guchelaar, H-J

    2015-10-01

    Breast cancer patients with absent or reduced CYP2D6 activity and consequently low endoxifen levels may benefit less from tamoxifen treatment. CYP2D6 poor and intermediate metabolizers may need a personalized increased tamoxifen dose to achieve effective endoxifen serum concentrations, without increasing toxicity. From a prospective study population of early breast cancer patients using tamoxifen (CYPTAM: NTR1509), 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during 2 months. The escalated dose was calculated by multiplying the individual's endoxifen level at baseline relative to the average endoxifen concentration observed in CYP2D6 extensive metabolizers by 20 mg (120 mg maximum). Endoxifen levels and tamoxifen toxicity were determined at baseline and after 2 months, just before patients returned to the standard dose of 20 mg. Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (p < 0.001; p = 0.002, respectively) without increasing side effects. In intermediate metabolizers, dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers. In poor metabolizers, the mean endoxifen level increased from 24 to 81 % of the mean concentration in extensive metabolizers. In all patients, the endoxifen threshold of 5.97 ng/ml (=16.0 nM) reported by Madlensky et al. was reached following dose escalation. CYP2D6 genotype- and endoxifen-guided tamoxifen dose escalation increased endoxifen concentrations without increasing short-term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long-term toxic effects is uncertain and needs to be explored. PMID:26369533

  17. 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.

  18. Association of tamoxifen use and ovarian function in patients with invasive or pre-invasive breast cancer.

    PubMed

    Chien, A Jo; Duralde, Erin; Hwang, Richard; Tsung, Karen; Kao, Chia-Ning; Rugo, Hope S; Melisko, Michelle E; Esserman, Laura J; Munster, Pamela N; Cedars, Marcelle; Kerlikowske, Karla; McCulloch, Charles E; Rosen, Mitch P

    2015-08-01

    The impact of long-term tamoxifen therapy on ovarian function is not known. Understanding these effects will help reproductive-aged patients who desire future pregnancy make more informed decisions regarding their treatment. This is a retrospective cohort study in patients identified through the UCSF Cancer Registry and SPORE database. We enrolled women with a history of ductal carcinoma in situ (DCIS) or early stage invasive breast cancer who were premenopausal at diagnosis and did not receive chemotherapy. Menstrual histories were obtained through electronic and paper surveys. We compared the age of menopause onset and menstrual pattern changes between women who received tamoxifen (TAM) and those who did not receive tamoxifen (control). Neither group received chemotherapy. 250 subjects were included in this study (125 TAM, 125 control). Mean age of menopause onset was 51.0 for both the groups and was not associated with duration of tamoxifen use or the age at tamoxifen initiation. Menstrual pattern changes, including amenorrhea, were more frequent in the TAM group than control group (any change: 48% TAM vs. 15 % control, p < 0.001; amenorrhea: 22% TAM vs. 3% control, p < 0.001). Older age was associated with an increased risk of developing amenorrhea within 6 months of starting tamoxifen (HR 1.32, p < 0.001). Menstrual pattern changes are common in premenopausal women taking tamoxifen. Tamoxifen use in the absence of chemotherapy is not associated with an earlier age onset of menopause in patients with DCIS or invasive breast cancer and is unlikely to significantly accelerate ovarian aging. PMID:26208485

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

    PubMed

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

    2010-06-01

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

  20. Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension

    PubMed Central

    Kim, Jae Hyun; Kim, Jung Min; Cho, Youn Zoo; Na, Ji Hoon; Kim, Hyun Sik; Kim, Hyoun A; Kang, Hye Won; Baik, Soon Koo; Kwon, Sang Ok; Cha, Seung Hwan; Kim, Young Ju

    2014-01-01

    Background/Aims Angiotensin receptor blockers (ARBs) inhibit activated hepatic stellate cell contraction and are thought to reduce the dynamic portion of intrahepatic resistance. This study compared the effects of combined treatment using the ARB candesartan and propranolol versus propranolol monotherapy on portal pressure in patients with cirrhosis in a prospective, randomized controlled trial. Methods Between January 2008 and July 2009, 53 cirrhotic patients with clinically significant portal hypertension were randomized to receive either candesartan and propranolol combination therapy (26 patients) or propranolol monotherapy (27 patients). Before and 3 months after the administration of the planned medication, the hepatic venous pressure gradient (HVPG) was assessed in both groups. The dose of propranolol was subsequently increased from 20 mg bid until the target heart rate was reached, and the candesartan dose was fixed at 8 mg qd. The primary endpoint was the HVPG response rate; patients with an HVPG reduction of >20% of the baseline value or to <12 mmHg were defined as responders. Results The mean portal pressure declined significantly in both groups, from 16 mmHg (range, 12-28 mmHg) to 13.5 mmHg (range, 6-20 mmHg) in the combination group (P<0.05), and from 17 mmHg (range, 12-27 mmHg) to 14 mmHg (range, 7-25 mmHg) in the propranolol monotherapy group (P<0.05). However, the medication-induced pressure reduction did not differ significantly between the two groups [3.5 mmHg (range, -3-11 mmHg) vs. 3 mmHg (range, -8-10 mmHg), P=0.674]. The response rate (55.6% vs. 61.5%, P=0.435) and the reductions in mean blood pressure or heart rate also did not differ significantly between the combination and monotherapy groups. Conclusions The addition of candesartan (an ARB) to propranolol confers no benefit relative to classical propranolol monotherapy for the treatment of portal hypertension, and is thus not recommended. PMID:25548744

  1. No effect on pharmacokinetics of tamoxifen and 4-hydroxytamoxifen by multiple doses of red clover capsule in rats

    PubMed Central

    Raju, Kanumuri Siva Rama; Taneja, Isha; Valicherla, Guru Raghavendra; Challagundla, Murali Krishna; Rashid, Mamunur; Syed, Anees Ahmed; Gayen, Jiaur Rahman; Singh, Sheelendra Pratap; Wahajuddin, Muhammad

    2015-01-01

    Tamoxifen is used in clinical practice for breast cancer patients and to prevent osteoporosis. Red clover (Trifolium pratense) preparations are consumed worldwide as dietary supplements for relieving postmenopausal symptoms. In the present study we investigated the possible herb-drug interaction between red clover and tamoxifen in rats. 15 days pre-treatment with red clover did not alter the tamoxifen and its active metabolite 4-hydroxytamoxifen pharmacokinetics significantly (p > 0.05). Therefore the therapeutic efficacy of the tamoxifen may not be compromised by the co-administration with red clover. Tamoxifen metabolism is primarily mediated by CYP2D6, CYP3A4 with minor contribution from CYP2C9, CYP2E1 and CYP1A2 isoforms. Although, red clover pre-treatment significantly (p < 0.05) decreased the mRNA expression and activity of CYP3a2, no effect on CYP2d4 and increased expression and activity of CYP2c11 could be the plausible reasons for lack of effect on tamoxifen and its metabolite pharmacokinetics in rats. CYP1a1 and CYP2b2 mRNA expression and activity were also significantly reduced by red clover. To extend the clinical utility of the present study, effect of red clover extract on major CYPs using human liver microsomes and HepG2 cell lines were also determined. Similar finding were observed in the human liver preparations as in rats. PMID:26530625

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

    PubMed

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

    2015-01-01

    A method was developed for the analysis of tamoxifen and its main derivatives (4-hydroxytamoxifen, N-desmethyl-tamoxifen, tamoxifen-N-oxide and endoxifen) in human plasma, using micellar liquid chromatography coupled with fluorescence detection. Analytes were off-line derivatized by sample UV-irradiation for 20 min to form the photocycled fluorescent derivatives. Then samples were diluted, filtered and directly injected, thus avoiding extraction steps. The analytes were resolved using a mobile phase containing 0.08 M SDS-4.5% butanol at pH 3 running at 1.5 mL/min through a C18 column at 40°C, without interferences from endogenous compounds in plasma. Excitation and emission wavelengths were 260 and 380 nm, respectively. The chromatographic analysis time was less than 40 min. The analytical methodology was validated following the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines in terms of: selectivity, linear range (0.3-15 μg/mL), linearity (r(2)>0.999), sensitivity (LOD, 65-80 ng/mL; LOQ, 165-200 ng/mL), intra- and interday accuracy (-12.2-11.5%) and precision (<9.2%) and robustness (<6.3%). The method was used to quantify the tamoxifen and tamoxifen derivatives in several breast cancer patients from a local hospital, in order to study the correlation between the genotype of the patient and the ability to metabolize tamoxifen. PMID:25281137

  3. 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

  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. PMID:26320721

  5. Drug Efflux Transporters Are Overexpressed in Short-Term Tamoxifen-Induced MCF7 Breast Cancer Cells

    PubMed Central

    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

  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. [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). PMID:26829860

  8. 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.

  9. 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...

  10. 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...

  11. 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...

  12. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 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...

  13. 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...

  14. 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...

  15. 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...

  16. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 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...

  17. 21 CFR 172.710 - Adjuvants for pesticide use dilutions.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Adjuvants for pesticide use dilutions. 172.710... 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 or applicant prior to application to...

  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. 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...

  20. 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...

  1. Effectiveness of spray adjuvants on reduction of spray drift

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  2. 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...

  3. 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...

  4. 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...

  5. p21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells

    PubMed Central

    Li, Zhilun; Lorent, Julie; Zhao, Chunyan; Dahlman-Wright, Karin; Strömblad, Staffan

    2015-01-01

    Estrogen receptor alpha (ERα) is highly expressed in most breast cancers. Consequently, ERα modulators, such as tamoxifen, are successful in breast cancer treatment, although tamoxifen resistance is commonly observed. While tamoxifen resistance may be caused by altered ERα signaling, the molecular mechanisms regulating ERα signaling and tamoxifen resistance are not entirely clear. Here, we found that PAK4 expression was consistently correlated to poor patient outcome in endocrine treated and tamoxifen-only treated breast cancer patients. Importantly, while PAK4 overexpression promoted tamoxifen resistance in MCF-7 human breast cancer cells, pharmacological treatment with a group II PAK (PAK4, 5, 6) inhibitor, GNE-2861, sensitized tamoxifen resistant MCF-7/LCC2 breast cancer cells to tamoxifen. Mechanistically, we identified a regulatory positive feedback loop, where ERα bound to the PAK4 gene, thereby promoting PAK4 expression, while PAK4 in turn stabilized the ERα protein, activated ERα transcriptional activity and ERα target gene expression. Further, PAK4 phosphorylated ERα-Ser305, a phosphorylation event needed for the PAK4 activation of ERα-dependent transcription. In conclusion, PAK4 may be a suitable target for perturbing ERα signaling and tamoxifen resistance in breast cancer patients. PMID:26554417

  6. 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.

  7. 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.

  8. Adjuvant steroids and relapse of typhoid fever.

    PubMed

    Cooles, P

    1986-10-01

    In a retrospective study, relapse after non-severe acute typhoid fever was highly significantly related to the use of adjuvant steroid in the initial illness. The steroid was given late and in small doses when compared with other studies. Caution should be observed when using steroids in this way as relapse though often mild may be a severe illness. PMID:3795323

  9. Aluminum vaccine adjuvants: are they safe?

    PubMed

    Tomljenovic, L; Shaw, C A

    2011-01-01

    Aluminum is an experimentally demonstrated neurotoxin and the most commonly used vaccine adjuvant. Despite almost 90 years of widespread use of aluminum adjuvants, medical science's understanding about their mechanisms of action is still remarkably poor. There is also a concerning scarcity of data on toxicology and pharmacokinetics of these compounds. In spite of this, the notion that aluminum in vaccines is safe appears to be widely accepted. Experimental research, however, clearly shows that aluminum adjuvants have a potential to induce serious immunological disorders in humans. In particular, aluminum in adjuvant form carries a risk for autoimmunity, long-term brain inflammation and associated neurological complications and may thus have profound and widespread adverse health consequences. In our opinion, the possibility that vaccine benefits may have been overrated and the risk of potential adverse effects underestimated, has not been rigorously evaluated in the medical and scientific community. We hope that the present paper will provide a framework for a much needed and long overdue assessment of this highly contentious medical issue. PMID:21568886

  10. Tamoxifen malabsorption after Roux-en-Y gastric bypass surgery: case series and review of the literature.

    PubMed

    Wills, Shannon M; Zekman, Richard; Bestul, Daniel; Kuwajerwala, Nafisa; Decker, David

    2010-02-01

    Roux-en-Y gastric bypass is a gastric reduction duodenal switch with a combination of restrictive and malabsorptive procedures. It is the most common gastric bypass procedure performed in the United States. Malabsorption causing nutritional deficiencies does occur, yet a PubMed literature search (1955-2009) returned no reports of malabsorption of anticancer agents after gastric bypass. To our knowledge, this is the first report of three cases of malabsorption of the anticancer agent tamoxifen after this procedure. The first patient was a 58-year-old woman who underwent Roux-en-Y bypass for morbid obesity. Two years later, she developed estrogen receptor-positive ductal carcinoma in situ of the breast, underwent lumpectomy and irradiation, and tamoxifen was started. Two years after that, she presented with concerns of potential malabsorption of the drug. Her plasma tamoxifen level was 28 ng/ml, which was below the lower limit of the therapeutic range (77-274 ng/ml for 10-30-mg/day regimens). The second patient was a 51-year-old woman who sought medical advice on risk reduction for breast cancer after receiving a diagnosis of atypical ductal hyperplasia of the breast. She also had a history of morbid obesity and underwent Roux-en-Y bypass. Tamoxifen was started to reduce her risk of breast cancer; her plasma tamoxifen level was subtherapeutic at 14 ng/ml. The third patient was a 53-year-old woman with estrogen receptor-positive breast cancer who underwent lumpectomy and was prescribed anastrozole, an aromatase inhibitor. She also underwent Roux-en-Y bypass for morbid obesity. As she experienced adverse effects while receiving anastrozole, the drug was discontinued, and tamoxifen 20 mg/day was started. Her tamoxifen plasma level was 52 ng/ml. Therefore, her tamoxifen dosage was increased to 20 mg twice/day. Six weeks later, her tamoxifen level was 120 ng/ml (therapeutic range 95-520 ng/ml for the increased dosage). These three cases suggest that steady-state serum

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. Pharmacogenetics of CYP2D6 and tamoxifen therapy: Light at the end of the tunnel?

    PubMed

    Del Re, M; Citi, V; Crucitta, S; Rofi, E; Belcari, F; van Schaik, R H; Danesi, R

    2016-05-01

    The clinical usefulness of assessing the enzymatic activity of CYPD6 in patients taking tamoxifen had been longly debated. In favour of preemptive evaluation of phenotypic profile of patients is the strong pharmacologic rationale, being that the formation of endoxifen, the major and clinically most important metabolite of tamoxifen, is largely dependent on the activity of CYP2D6. This enzyme is highly polymorphic for which the activity is largely depending on genetics, but that can also be inhibited by a number of drugs, i.e. antidepressants, which are frequently used in patients with cancer. Unfortunately, the clinical trials that have been published in the last years are contradicting each other on the association between CYP2D6 and significant clinical endpoints, and for this reason CYP2D6 genotyping is at present not generally recommended. Despite this, the CYP2D6 genotyping test for tamoxifen is available in many laboratories and it may still be an appropriate test to use it in specific cases. PMID:27060675

  17. 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.

  18. Tamoxifen nanostructured lipid carriers: enhanced in vivo antitumor efficacy with reduced adverse drug effects.

    PubMed

    Shete, Harshad K; Selkar, Nilakash; Vanage, Geeta R; Patravale, Vandana B

    2014-07-01

    A novel approach of enhancing the Tamoxifen uptake via Intestinal Lymphatic System is executed by developing long chain lipid and oil based nanostructured lipid carrier system (Tmx-NLC). The aim was to achieve improved systemic bioavailability of Tamoxifen, prevent systemic and hepatotoxicity and enhance antitumor efficacy. Following the proof of concept achieved in cell culture experiments and in vivo pharmacokinetic and biodistribution study, the current work focuses on investigation of antitumor efficacy and treatment associated toxicity in murine mammary tumor mice model. The efficacy study demonstrated greater tumor suppression and 100% survival with 1.5 and 3 mg/kg Tmx-NLC compared to 3 mg/kg Tamoxifen suspension and Mamofen(®) (Khandelwal Pharmaceuticals, Mumbai, India). Tmx-NLC treatment for a month demonstrated improved systemic toxicity profile and no evidences of hepatotoxicity. Thus, developed Tmx-NLC could prove to be a promising delivery strategy to confer superior therapeutic efficacy and ability to address the biopharmaceutical and toxicity associated issues of drug. PMID:24704438

  19. 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

  20. 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

  1. Combined tamoxifen and gefitinib in non-small cell lung cancer shows antiproliferative effects.

    PubMed

    Shen, Hua; Yuan, Yuan; Sun, Jing; Gao, Wen; Shu, Yong-Qian

    2010-02-01

    Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is approved for clinical use in the treatment of non-small cell lung cancer (NSCLC). According to statistics, NSCLC patients who are female, have adenocarcinoma, or never smoked have a higher response rate to gefitinib treatment. This phenomenon could be due to the interaction between the estrogen receptor (ER) and EGFR. To test whether inhibition of the EGFR signaling pathway affects the antitumour effect of gefitinib, NSCLC cell lines were treated with gefitinib and tamoxifen, an ER antagonist. Cotreatment with gefitinib plus tamoxifen decreased the proliferation and increased the apoptosis of A549 and H1650 adencarcinoma cell lines, when compared with either drug alone. However, there was no effect on H520 cells (squamous cell carcinoma). Rapid activation of the EGFR pathway by both EGF and beta-E2 was observed in A549 cells. Additionally, EGFR and ERbeta expression was down-regulated in response to estrogen and EGF, respectively, but up-regulated in response to tamoxifen and genfitib, respectively. These results suggest that there is a functional cross-signaling between the EGFR and the ER pathways in NSCLC, possibly providing a rationale to combine gefitinib with anti-estrogen therapy for lung cancer treatment. PMID:20005069

  2. 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

  3. Reduction of Breast Density Following Tamoxifen Treatment Evaluated by 3-D MRI: Preliminary Study

    PubMed Central

    Chen, Jeon-Hor; Chang, Yeun-Chung; Chang, Daniel; Wang, Yi-Ting; Nie, Ke; Chang, Ruey-Feng; Nalcioglu, Orhan; Huang, Chiun-Sheng; Su, Min-Ying

    2010-01-01

    This study analyzed the change of breast density in women receiving tamoxifen treatment using 3-D MRI. Sixteen women were studied. Each woman received breast MRI before and after tamoxifen. The breast and the fibroglandular tissue were segmented using a computer-assisted algorithm, based on T1-weighted images. The fibroglandular tissue volume (FV) and breast volume (BV) were measured and the ratio was calculated as the percent breast density (%BD). The changes in breast volume (ΔBV), fibroglandular tissue volume (ΔFV), and percent density (Δ%BD) between two MRI studies were analyzed and correlated with treatment duration and baseline breast density. The ΔFV showed a reduction in all 16 women. The Δ%BD showed a mean reduction of 5.8%. The reduction of FV was significantly correlated with baseline FV (P<0.001) and treatment duration (P=0.03). The percentage change in FV was correlated with duration (P=0.049). The reduction in %BD was positively correlated with baseline %BD (p=0.02). Women with higher baseline %BD showed more reduction of %BD. 3D MRI may be useful for the measurement of the small changes of ΔFV and Δ%BD after tamoxifen. These changes can potentially be used to correlate with the future reduction of cancer risk. PMID:20832226

  4. 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

  5. Tamoxifen Prevents Apoptosis and Follicle Loss from Cyclophosphamide in Cultured Rat Ovaries1

    PubMed Central

    Piasecka-Srader, Joanna; Blanco, Fernando F.; Delman, Devora H.; Dixon, Dan A.; Geiser, James L.; Ciereszko, Renata E.; Petroff, Brian K.

    2015-01-01

    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

  6. 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

  7. 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

  8. Impact of UGT2B7 His268Tyr polymorphism on the outcome of adjuvant epirubicin treatment in breast cancer

    PubMed Central

    2011-01-01

    Introduction Epirubicin is a common adjuvant treatment for breast cancer. It is mainly eliminated after glucuronidation through uridine diphosphate-glucuronosyltransferase 2B7 (UGT2B7). The present study aimed to describe the impact of the UGT2B7His268Tyr polymorphism on invasive disease-free survival in breast cancer patients after epirubicin treatment. Methods This is a pharmacogenetic study based on samples collected from 745 breast cancer patients of the Austrian Tumor of breast tissue: Incidence, Genetics, and Environmental Risk factors (TIGER) cohort who did not present metastases at baseline. This cohort included 205 women with epirubicin-based combination chemotherapy, 113 patients having received chemotherapy without epirubicin and 427 patients having received no chemotherapy at all. Of the epirubicin-treated subgroup, 120 were subsequently treated with tamoxifen. For all women UGT2B7His268Tyr was genotyped. Invasive disease-free survival was assessed using Kaplan-Meier and Cox's proportional hazard regression analysis. Results Among the 205 epirubicin-treated patients, carriers of two UGT2B7268Tyr alleles had a mean invasive disease-free survival of 8.6 (95% confidence interval (CI) 7.9 to 9.3) years as compared to 7.5 (95% CI 6.9 to 8.0) years in carriers of at least one UGT2B7268His allele (adjusted hazard ratio (HR) = 2.64 (95% CI 1.22 to 5.71); P = 0.014). In addition, the impact of the UGT2B7His268Tyr polymorphism became even more pronounced in patients subsequently treated with tamoxifen (adjusted HR = 5.22 (95% CI 1.67 to 26.04); P = 0.015) whereas no such difference in invasive disease-free survival was observed in patients not receiving epirubicin. Conclusions Breast cancer patients carrying the UGT2B7268Tyr/Tyr genotype may benefit most from adjuvant epirubicin-based chemotherapy. These results warrant confirmation in further studies. PMID:21658222

  9. 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

  10. 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

  11. Risk Factors for Treatment Failure of Polymyxin B Monotherapy for Carbapenem-Resistant Klebsiella pneumoniae Infections

    PubMed Central

    Dubrovskaya, Yanina; Scipione, Marco R.; Esaian, Diana; Phillips, Michael S.; Papadopoulos, John; Mehta, Sapna A.

    2013-01-01

    Polymyxins are reserved for salvage therapy of infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). Though synergy has been demonstrated for the combination of polymyxins with carbapenems or tigecycline, in vitro synergy tests are nonstandardized, and the clinical effect of synergy remains unclear. This study describes outcomes for patients with CRKP infections who were treated with polymyxin B monotherapy. We retrospectively reviewed the medical records of patients with CRKP infections who received polymyxin B monotherapy from 2007 to 2011. Clinical, microbiology, and antimicrobial treatment data were collected. Risk factors for treatment failure were identified by logistic regression. Forty patients were included in the analysis. Twenty-nine of 40 (73%) patients achieved clinical cure as defined by clinician-documented improvement in signs and symptoms of infections, and 17/32 (53%) patients with follow-up culture data achieved microbiological cure. End-of-treatment mortality was 10%, and 30-day mortality was 28%. In a multivariate analysis, baseline renal insufficiency was associated with a 6.0-fold increase in clinical failure after adjusting for septic shock (odds ratio [OR] = 6.0; 95% confidence interval [CI] = 1.22 to 29.59). Breakthrough infections with organisms intrinsically resistant to polymyxins occurred in 3 patients during the treatment. Eighteen of 40 (45%) patients developed a new CRKP infection a median of 23 days after initial polymyxin B treatment, and 3 of these 18 infections were polymyxin resistant. The clinical cure rate achieved in this retrospective study was 73% of patients with CRKP infections treated with polymyxin B monotherapy. Baseline renal insufficiency was a risk factor for treatment failure after adjusting for septic shock. Breakthrough infections with organisms intrinsically resistant to polymyxin B and development of resistance to polymyxin B in subsequent CRKP isolates are of concern. PMID:23959321

  12. 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.

  13. HIV-1 subtype influences susceptibility and response to monotherapy with the protease inhibitor lopinavir/ritonavir

    PubMed Central

    Sutherland, K. A.; Ghosn, J.; Gregson, J.; Mbisa, J. L.; Chaix, M. L.; Cohen Codar, I.; Delfraissy, J. F.; Delaugerre, C.; Gupta, R. K.

    2015-01-01

    Objective PI susceptibility results from a complex interplay between protease and Gag proteins, with Gag showing wide variation across HIV-1 subtypes. We explored the impact of pre-treatment susceptibility on the outcome of lopinavir/ritonavir monotherapy. Methods Treatment-naive individuals who experienced lopinavir/ritonavir monotherapy failure from the MONARK study were matched (by subtype, viral load and baseline CD4 count) with those who achieved virological response (‘successes’). Successes were defined by viral load <400 copies/mL after week 24 and <50 copies/mL from week 48 to week 96. Full-length Gag–protease was amplified from patient samples for in vitro phenotypic susceptibility testing, with susceptibility expressed as fold change (FC) relative to a subtype B reference strain. Results Baseline lopinavir susceptibility was lower in viral failures compared with viral successes, but the differences were not statistically significant (median lopinavir susceptibility: 4.4 versus 8.5, respectively, P = 0.17). Among CRF02_AG/G patients, there was a significant difference in lopinavir susceptibility between the two groups (7.1 versus 10.4, P = 0.047), while in subtype B the difference was not significant (2.7 versus 3.4, P = 0.13). Subtype CRF02_AG/G viruses had a median lopinavir FC of 8.7 compared with 3.1 for subtype B (P = 0.001). Conclusions We report an association between reduced PI susceptibility (using full-length Gag–protease sequences) at baseline and subsequent virological failure on lopinavir/ritonavir monotherapy in antiretroviral-naive patients harbouring subtype CRF02_AG/G viruses. We speculate that this may be important in the context of suboptimal adherence in determining viral failure. PMID:25228587

  14. SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines

    PubMed Central

    Srivastava, Abhishek K.; Dinc, Gunes; Sharma, Rajesh K.; Yolcu, Esma S.; Zhao, Hong; Shirwan, Haval

    2014-01-01

    Vaccines based on tumor-associated antigens (TAA) have limited therapeutic efficacy due to their weak immunogenic nature and the various immune evasion mechanisms active in advanced tumors. In an effort to overcome these limitations, we evaluated a combination of the T cell co-stimulatory molecule SA-4-1BBL with the TLR4 agonist monophosphoryl lipid A (MPL) as a novel vaccine adjuvant system. In the TC-1 mouse allograft model of HPV-induced cancer, a single administration of this combination adjuvant with HPV E7 protein caused tumor rejection in all tumor-bearing mice. On its own, SA-4-1BBL outperformed MPL in this setting. Against established tumors, two vaccinations were sufficient to elicit rejection in the majority of mice. In the metastatic model of Lewis lung carcinoma, vaccination of the TAA survivin with SA-4-1BBL/MPL yielded superior efficacy against pulmonary metastases. Therapeutic efficacy of SA-4-1BBL/MPL was achieved in the absence of detectable toxicity, correlating with enhanced DC activation, CD8+ T cell function and an increased intratumoral ratio of CD8+ T effector cells to CD4+FoxP3+ T regulatory cells. Unexpectedly, use of MPL on its own was associated with unfavorable intratumoral ratios of these T cell populations resulting in suboptimal efficacy. The efficacy of MPL monotherapy was restored by depletion of T regulatory cells, whereas eliminating CD8+ T cells abolished the efficacy of its combination with SA-4-1BBL. Mechanistic investigations showed that IFN-γ played a critical role in supporting the therapeutic effect of SA-4-1BBL/MPL. Taken together, our results offer a preclinical proof of concept for the use of a powerful new adjuvant system for TAA-based cancer vaccines. PMID:25252915

  15. 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

  16. Genotoxicity evaluation in patients on phenobarbital monotherapy by sister chromatid exchange.

    PubMed

    Schaumann, B A; Winge, V B; Pederson, M

    1989-01-01

    The potential of phenobarbital to interact with DNA has been studied using the sister chromatid exchange (SCE) assay in peripheral lymphocytes of nine adult male patients with epilepsy and of their matched controls. All patients were otherwise healthy individuals, treated chronically with phenobarbital in monotherapy. No statistically significant differences in SCE levels were found between the patient and control groups. Smoking was associated with increased SCE frequencies. The experiment was repeated with five available patients, using a slightly modified methodology. Although different SCE scores were obtained, the results of both tests were comparable. PMID:2585535

  17. 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

  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. 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

  20. ER-α36, a novel variant of ERα, is involved in the regulation of Tamoxifen-sensitivity of glioblastoma cells.

    PubMed

    Liu, Yang; Huang, Liang; Guan, Xin; Li, Hongyan; Zhang, Qi-Qi; Han, Chao; Wang, Ya-Jun; Wang, Cui; Zhang, Yejun; Qu, Chao; Liu, Jing; Zou, Wei

    2016-07-01

    Although accumulating evidence has confirmed that adjuvant Tamoxifen (TAM) treatment is able to sensitize glioblastoma cells to radiotherapy and inhibit their proliferation, TAM is not a suitable treatment for all types of glioblastoma cells; furthermore, long-term TAM usage may lead to TAM resistance. Therefore, understanding the underlying molecular mechanism of TAM resistance is necessary in order to improve TAM clinical therapy and the quality of life of patients suffering from glioblastomas. In this study, the significance of ER-α36 to TAM resistance in glioblastoma cells was examined. First, an analysis of ER-α36 expression in two glioblastoma cell lines U87-MG and U251, showed that ER-α36 was anchored to the cytoplasmic membrane of these cells via Caveolin-1. Subsequent experiments investigating the mechanism of TAM-induced inhibition of U87-MG cell growth showed that TAM exerts its effect by inducing apoptosis via a down-regulation of Survivin expression and an up-regulation of Caspase-3 expression. Furthermore, TAM also arrested the cell cycle at S-phase. However, when U87-MG cells were preconditioned with an ER-α36-specific agonist, IC162, this neutralized TAM-induced inhibition of cell growth. This contrasted with the effect of ER-α36 depletion by RNAi, which enhanced TAM-induced inhibition of cell growth. These findings suggest that resistance to TAM involves ER-α36, which probably acts as a negative regulator of TAM-induced inhibition of glioblastoma cell growth. These findings provide a novel insight into the basis of TAM resistance during glioblastoma therapy and a further study is underway to reveal more about the specific molecular mechanisms associated with ER-α36-mediated TAM resistance. PMID:26898538

  1. 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. PMID:26923756

  2. 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

  3. A Randomized Control Trial Comparing the Efficacy of Antiandrogen Monotherapy: Flutamide vs. Bicalutamide.

    PubMed

    Nakai, Yasushi; Tanaka, Nobumichi; Anai, Satoshi; Miyake, Makito; Tatsumi, Yoshihiro; Fujimoto, Kiyohide

    2015-08-01

    The study aims to compare serial changes in prostate-specific antigen (PSA), testosterone, dehydroepiandrosterone (DHEA), and androstenedione in patients treated with either of the antiandrogen agents, bicalutamide or flutamide, using a randomized controlled study. Patients had to meet the following inclusion criteria: (1) presence of histopathologically confirmed prostate cancer, (2) prostate cancer treatment naive, (3) no current treatment with luteinizing hormone-releasing hormone (LH-RH) agonist for sexual interest and physical capacity, (4) clinical stage T1-cT3N0M0, (5) Gleason score ≤ 7, and (6) Cooperative Oncology Group performance status 0-1. Patients were randomly allocated to two groups: flutamide and bicalutamide monotherapy group 1:1. PSA levels were significantly decreased in both groups at 4 weeks. PSA levels were significantly lower in the bicalutamide group compared with the flutamide group at 4 and 8 weeks. Testosterone levels in the bicalutamide group were significantly higher than the baseline levels between 4 and 24 weeks of treatment. Testosterone levels in the flutamide group were significantly increased at 4 and 12 weeks and returned to baseline levels at 16 and 24 weeks. DHEA levels in the bicalutamide group were unchanged from baseline at 4 and 24 weeks. However, DHEA levels in the flutamide group were decreased at 24 weeks. Androstenedione levels increased slightly in both groups, but the increase did not reach statistical significance. PSA, testosterone, and DHEA levels significantly differed between bicalutamide and flutamide monotherapy. PMID:26024831

  4. Duration of valproic acid monotherapy correlates with subclinical thyroid dysfunction in children with epilepsy.

    PubMed

    Ilić, Violeta; Bogićević, Dragana; Miljković, Branislava; Ješić, Maja; Kovačević, Marijana; Prostran, Milica; Kovačević, Sandra Vezmar

    2016-06-01

    To identify potential risk factors for the development of subclinical hypothyroidism following long-term valproic acid monotherapy in children with epilepsy. Serum levels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine, thyreoglobulin antibodies, and thyroid peroxidase antibodies were determined in 41 patients and in 41 sex- and age-matched healthy children. Mean valproic acid treatment duration was 2.80±1.96 years. The valproic acid group had higher serum thyroid-stimulating hormone (p<0.001) and free triiodothyronine (p<0.05) levels compared to the control group. Serum thyroid-stimulating hormone and free triiodothyronine were above the upper limit for healthy controls in 34% and 32% of patients, respectively, and no clinical features of thyroid dysfunction were observed. Duration of valproic acid monotherapy for less than four years was a risk factor for elevated thyroid-stimulating hormone levels. One third of children with normal range serum valproic acid levels may have elevated serum thyroid-stimulating hormone and free triiodothyronine levels, especially in the first four years of treatment. PMID:27099936

  5. 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. PMID:27049102

  6. 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

  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. CRIM-negative infantile Pompe disease: Characterization of immune responses in patients treated with ERT monotherapy

    PubMed Central

    Berrier, Kathryn L.; Kazi, Zoheb B.; Prater, Sean N.; Bali, Deeksha S.; Goldstein, Jennifer; Stefanescu, Mihaela C.; Rehder, Catherine W.; Botha, Eleanor G.; Ellaway, Carolyn; Bhattacharya, Kaustuv; Tylki-Szymanska, Anna; Karabul, Nesrin; Rosenburg, Amy S.; Kishnani, Priya S.

    2015-01-01

    Purpose Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross reactive immunologic material (CRIM)-negative (CN) patients have immune responses with significant clinical decline despite continued ERT. We aimed to characterize immune responses in CN IPD patients receiving ERT monotherapy. Methods A chart review identified 20 CN IPD patients treated with ERT monotherapy for ≥6 months. Patients were stratified by anti-rhGAA antibody titers: high sustained antibody titers (HSAT) ≥51,200 at least twice; low titers (LT) <6,400 throughout treatment; or sustained intermediate titers (SIT) 6,400–25,600. Results Despite early initiation of treatment, the majority (85%) of CN patients developed significant antibody titers, most with HSAT associated with invasive ventilation and death. Nearly all patients with HSAT had at least one nonsense GAA mutation, while the LT group exclusively carried splice site or frameshift mutations. Only one patient in the HSAT group is currently alive after successful immune modulation in the entrenched setting. Conclusion Immunological responses are a significant risk in CN IPD; thus, immune tolerance induction in the naïve setting should strongly be considered. Further exploration of factors influencing immune responses is required, particularly with the advent of newborn screening for Pompe disease. PMID:25741864

  9. 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

  10. 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

  11. 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

  12. [A case of recurrent breast cancer successfully treated with capecitabine monotherapy].

    PubMed

    Mitsuyama, Shoshu; Anan, Keisei; Ono, Minoru

    2005-08-01

    A 51-year-old woman underwent pectoralis-preserving mastectomy for right breast cancer (squamous cell cancer, f, T1c, ly0, v0, N2 (18/33), p53 (3+), HER2 (2+), ER (-), PgR (-), T1cN2M0 (Stage IIIA) in March 2001, and received systemic chemotherapy using doxorubicin combined with cyclophosphamide, followed by paclitaxel. After chemotherapy, radiotherapy was added to the chest wall, supraclavicular and parasternal regions. In March 2002 (disease-free interval of one year), liver metastasis was revealed. Systemic therapy using docetaxel, and hepatic artery infusion therapy with epirubicin following docetaxel, failed. Since June 2003, capecitabine monotherapy (2,400 mg/day) was initiated for the liver and lymph node metastases in the mediastinum and retroperitoneum. After 3 cycles, all metastases responded and a marked response has been maintained for 15 months. This therapy is being continued (18 cycles), and no serious side effects have been encountered. Capecitabine monotherapy is safe and very useful for recurrent breast cancer. PMID:16121919

  13. 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

  14. The adjuvancy of silicones: dependency on compartmentalization.

    PubMed

    Klykken, P C; White, K L

    1996-01-01

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

  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. 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.

  17. Tamoxifen enhances the differentiation-inducing and growth-inhibitory effects of all-trans retinoic acid in acute promyelocytic leukemia cells.

    PubMed

    Adachi, Koji; Honma, Yoshio; Miyake, Takaaki; Kawakami, Koshi; Takahashi, Tsutomu; Suzumiya, Junji

    2016-03-01

    All-trans retinoic acid (ATRA) is valuable in differentiation therapy for acute promyelocytic leukemia (APL). However, ATRA has had limited success as a single agent, due to the development of resistance. We found that tamoxifen effectively enhanced the differentiation-inducing effect of ATRA. Tamoxifen alone inhibited the proliferation of myeloid leukemia cell lines while only slightly increasing morphologic differentiation. Tamoxifen effectively enhanced the growth-inhibiting actions of various differentiation-inducing agents. ATRA in the presence of tamoxifen increased NBT reduction and the expression of CD11b in HL-60 cells more effectively than ATRA alone. Tamoxifen also enhanced the differentiation induced by the other inducers tested. ATRA induced the differentiation of APL cell lines NB4 and HT93 and APL cells in primary culture, and this differentiation was also enhanced by tamoxifen. Tamoxifen is one of the most widely used drugs for the treatment of cancer and has few side effects. The combination of ATRA and tamoxifen might be considered for the treatment of APL patients in whom it can be difficult to apply arsenic trioxide or anthracyclines. PMID:26797574

  18. Ovarian endometrioid carcinoma and endometriosis developing in a postmenopausal breast cancer patient during tamoxifen therapy: a case report and review of the literature.

    PubMed

    Cohen, I; Altaras, M M; Lew, S; Tepper, R; Beyth, Y; Ben-Baruch, G

    1994-12-01

    We present the first case of ovarian endometrioid carcinoma and endometriosis in a postmenopausal patient who was treated with tamoxifen for breast cancer. The association with prolonged unopposed estrogen-like stimulation with tamoxifen as a possible factor in the development of ovarian endometrioid carcinoma is discussed. PMID:7835785

  19. Melanoma and IFN alpha: potential adjuvant therapy.

    PubMed

    Bottoni, U; Clerico, R; Paolino, G; Corsetti, P; Ambrifi, M; Brachini, A; Richetta, A; Nisticò, S; Pranteda, G; Calvieri, S

    2014-01-01

    Interferon alpha (IFNalpha) is the most used adjuvant treatment in clinical practice for melanoma (MEL) high-medium risk patients; however, the use of IFNalpha has yielded conflicting data on Overall Survival (OS) and disease free survival (DFS) rates. Starting from these considerations, we carried out an analysis on our MEL patients who received adjuvant IFNalpha therapy, in order to identify possible predictors for their outcome. A total of 140 patients were included in our analysis. Patients with Breslow thickness ≤2.00 mm presented a significantly longer mean DFS than patients with Breslow ≥2.01 mm (p = 0.01). Using non- parametric Spearman’s Coefficient test we found association between DFS and Breslow thickness (p < 0.001) and between DFS and ulceration (p = 0.03). Performing Multiple Regression test, Breslow thickness (p < 0.001) remained the only statistically significant predictor. From the OS analysis we found that patients with lower Breslow values ≤ 2.00 mm (p < 0.0001), and absence of ulceration (p <0.004) showed a significantly better long-term survival. From the current analysis we found that the use of low dose IFNalpha is justified only for cutaneous melanoma ≤ 4.01 mm that was not ulcerated; patients with Breslow ≥ 4.01 mm, in our opinion, should not carry out adjuvant treatment with low dose IFNalpha, because its side effects could be higher than the its benefits. PMID:25001659

  20. 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

  1. 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

  2. Efficacy of live adjuvanted mesogenic Newcastle disease vaccine in chickens.

    PubMed

    Roy, P; Venugopalan, A T; Koteeswaran, A

    1999-06-01

    120 white leghorn chickens primed with a lentogenic Newcastle disease (ND) live vaccine at 7 days of age were divided into three equal groups of 8 weeks of age and vaccinated with a live mesogenic ND vaccine (NDV). One group received only Newcastle disease mesogenic vaccine (RDVK) in normal saline, the second group received RDVK with groundnut oil as adjuvant and the third group received RDVK with liquid paraffin as adjuvant. Sera were collected at different time points for the assessment of antibody level against ND virus (NDV) by the haemagglutination inhibition (HI) test. The commonly used non-adjuvanted RDVK could not evince 100% protective HI titre beyond 11 weeks of age but in both the adjuvanted groups 100% protective HI titre was evident up to 20 weeks of age. On challenge at 20 weeks of age both the adjuvanted groups withstood challenge but in the non-adjuvanted group 80% of chickens withstood the challenge. A significant difference in immune response between the adjuvanted and non-adjuvanted groups was seen but not between both the adjuvanted groups. The advantage of vegetable oil (groundnut oil) as an adjuvant for live mesogenic ND vaccine has been discussed. PMID:10418918

  3. 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

  4. Adjuvant chemotherapy for early-stage cervical cancer

    PubMed Central

    Asano, Hiroshi; Todo, Yukiharu; Watari, Hidemichi

    2016-01-01

    The aim of this review is to address the current status of adjuvant chemotherapy alone in early-stage cervical cancer treatments in the literature. At present, the therapeutic effect of adjuvant chemotherapy alone after radical surgery (RS) has not yet been established, and radiation therapy (RT) or concurrent chemoradiotherapy (CCRT) is recommended as the standard adjuvant therapy after RS for early-stage cervical cancer in various guidelines. The main purpose of adjuvant therapy after RS, however, should be to reduce extrapelvic recurrence rather than local recurrence, although adjuvant RT or CCRT has survival benefits for patients with intermediate- or high-risk factors for recurrence. Moreover, several studies reported that adjuvant therapies including RT were associated with a higher incidence of complications, such as lymphedema, bowel obstruction and urinary disturbance, and a lower grade of long-term quality of life (QOL) or sexual functioning than adjuvant chemotherapy alone. The effect of adjuvant chemotherapy alone for early-stage cervical cancer with intermediate- or high-risk factors for recurrence were not fully investigated in prospective studies, but several retrospective studies suggest that the adjuvant effects of chemotherapy alone are at least similar to that of RT or CCRT in terms of recurrence rate, disease-free survival, or overall survival (OS) with lower incidence of complications. Whereas cisplatin based combination regimens were used in these studies, paclitaxel/cisplatin (TP) regimen, which is currently recognized as a standard chemotherapy regimen for patients with metastatic, recurrent or persistent cervical cancer by Gynecologic Oncology Group (GOG), had also survival benefit as an adjuvant therapy. Therefore, it may be worth considering a prospective randomized controlled trial (RCT) of adjuvant chemotherapy alone using TP regimen versus adjuvant RT as an alternative adjuvant therapy. Because early-stage cervical cancer is a curable

  5. 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.

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

    PubMed

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

    2016-02-01

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

  7. 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

  8. Population pharmacokinetic modelling to assess the impact of CYP2D6 and CYP3A metabolic phenotypes on the pharmacokinetics of tamoxifen and endoxifen

    PubMed Central

    ter Heine, Rob; Binkhorst, Lisette; de Graan, Anne Joy M; de Bruijn, Peter; Beijnen, Jos H; Mathijssen, Ron H J; Huitema, Alwin D R

    2014-01-01

    Aims Tamoxifen is considered a pro-drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen. Methods We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non-linear mixed effects modelling. Results Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in endoxifen formation (inter-individual variability reduced from 55% to 25%). Conclusions We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug–drug interactions with tamoxifen without the necessity of administering this anti-oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice. PMID:24697814

  9. 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

  10. Working together: interactions between vaccine antigens and adjuvants

    PubMed Central

    Kramer, Ryan M.; Barnes V, Lucien; Dowling, Quinton M.; Vedvick, Thomas S.

    2013-01-01

    The development of vaccines containing adjuvants has the potential to enhance antibody and cellular immune responses, broaden protective immunity against heterogeneous pathogen strains, enable antigen dose sparing, and facilitate efficacy in immunocompromised populations. Nevertheless, the structural interplay between antigen and adjuvant components is often not taken into account in the published literature. Interactions between antigen and adjuvant formulations should be well characterized to enable optimum vaccine stability and efficacy. This review focuses on the importance of characterizing antigen–adjuvant interactions by summarizing findings involving widely used adjuvant formulation platforms, such as aluminum salts, emulsions, lipid vesicles, and polymer-based particles. Emphasis is placed on the physicochemical basis of antigen–adjuvant associations and the appropriate analytical tools for their characterization, as well as discussing the effects of these interactions on vaccine potency. PMID:24757512

  11. 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

  12. Tamoxifen-associated hot flash severity is inversely correlated with endoxifen concentration and CYP3A4*22.

    PubMed

    Baxter, Simon D; Teft, Wendy A; Choi, Yun-Hee; Winquist, Eric; Kim, Richard B

    2014-06-01

    Tamoxifen use is often limited in some patients due to adverse effects including severe hot flash symptoms. Tamoxifen undergoes hepatic bioactivation by CYP2D6 and CYP3A4 to form the active metabolite endoxifen. It remains unclear whether the extent of attained endoxifen level or genetic polymorphisms in drug metabolizing enzymes is associated with the frequency and severity of hot flashes. We conducted a prospective study using self-reported surveys to assess tamoxifen side effects experienced during the week prior to clinic visits of 132 female breast cancer patients on tamoxifen therapy, and hot flash severity scores were tabulated. At the time of clinic visit, blood samples were obtained to determine tamoxifen and its metabolite levels and to determine CYP2D6 and CYP3A4 genotypes. The majority of participants (77 %) experienced hot flashes, with 11 % experiencing severe or very severe symptoms. We observed an inverse correlation between endoxifen concentration and hot flash severity score following adjustment for age, BMI, and menopausal status in patients with non-zero scores (p < 0.001). Interestingly, CYP2D6 genotype was not significantly associated with hot flash scores in patients on no known inhibitory medications. However, CYP3A4*22 carriers were less likely to have hot flashes with an odds ratio of 8.87 (p < 0.01) even when compared to a cohort with similar endoxifen levels. Our data demonstrate that patients with higher endoxifen levels tended to predict lower hot flash severity scores. Importantly, this is the first study to show CYP3A4*22 genotype as an independent predictor of hot flash severity during tamoxifen therapy. PMID:24744093

  13. Efficacy of nonestrogenic hot flash therapies among women stratified by breast cancer history and tamoxifen use: a pooled analysis

    PubMed Central

    Bardia, Aditya; Novotny, Paul; Sloan, Jeff; Barton, Deb; Loprinzi, Charles

    2014-01-01

    Objective Various nonestrogenic therapies have been found to be effective in mitigating hot flashes, but it has been unclear whether the efficacy varies by whether women have had breast cancer and/or were taking tamoxifen. Methods This study used data from Mayo Clinic/North Central Cancer Treatment Group clinical trials that evaluated the efficacy of any nonestrogenic agent for hot flashes and had information on breast cancer history or tamoxifen use. Statistically significant changes from the fourth treatment week versus the baseline week, using individual patient data, were assessed using Student’s t test. Results A total of 1,396 women from 20 hot flash studies were eligible for analysis. Overall, women without breast cancer had a similar percentage of baseline hot flash score at week 4, as did those with breast cancer (53% vs 50%, P = 0.92). Women who were not taking tamoxifen had a significantly lower percentage of hot flash score at week 4 as compared with those who used tamoxifen (54% vs 61%, P = 0.01). However, this was due to a higher reduction in hot flash scores in the placebo arms among women not receiving tamoxifen; the percentage reduction in hot flash scores at week 4 from baseline in the active therapy arms of the randomized placebo-controlled trials (ie, excluding placebo arms) was similar among the tamoxifen users and nonusers (difference in mean percentage reduction, 5.7; 95% CI, −1.76 to 13.16). Conclusions Some nonestrogenic therapies seem to be useful for reducing hot flashes, irrespective of the etiology of hot flashes. PMID:19188850

  14. 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

  15. 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

  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. PMID:27077909

  17. Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures

    PubMed Central

    Taylor, Stephen; Smith, Catrin Tudur; Williamson, Paula R; Marson, Anthony G

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 4, 2001. Worldwide, phenytoin and phenobarbitone are commonly used antiepileptic drugs. They are more likely to be used in the developing world than the developed world, primarily because they are inexpensive. The aim of this review is to summarize data from existing trials comparing phenytoin and phenobarbitone. Objectives To review the effects of phenobarbitone compared to phenytoin when used as monotherapy in patients with partial onset seizures or generalized tonic-clonic seizures with or without other generalized seizure types. Search methods We searched the Cochrane Epilepsy Group trials register (20 October 2009), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2009) and MEDLINE (1950 to October week 2, 2009). In addition, we handsearched relevant journals, and contacted pharmaceutical companies and researchers in the field to seek any ongoing or unpublished studies. Selection criteria Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenobarbitone monotherapy with phenytoin monotherapy. Data collection and analysis This was an individual patient data review. Outcomes were time to (a) withdrawal of allocated treatment, (b) 12-month remission and (c) first seizure post randomization. Data were analyzed using a stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR > 1 indicates an event is more likely to occur earlier on phenobarbitone than phenytoin. Main results To date, data have been obtained for four of ten studies meeting the inclusion criteria, amounting to 599 individuals, or approximately 65% of the potential data. The main overall results (HR) were (a) time to treatment withdrawal 1.62 (95% confidence interval 1.22 to 2.14); (b) time to 12-month

  18. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome

    PubMed Central

    Kargiotis, Konstantinos; Athyros, Vasilios G; Giouleme, Olga; Katsiki, Niki; Katsiki, Evangelia; Anagnostis, Panagiotis; Boutari, Chrysoula; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

    2015-01-01

    AIM: To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis (NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH. METHODS: This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome (MetS) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients received lifestyle advice and were treated for a 12 mo period with rosuvastatin (10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid (SUA), high sensitivity C reactive protein (hsCRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values. RESULTS: The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20th, which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3rd treatment month (ANOVA P < 0.001), while alkaline phosphatase activities by the 6th treatment month (ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced (P < 0.001). Lipid values were normalised by the 3rd treatment month. No patient had MetS by the 9th treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and

  19. Benefit of low-dose tamoxifen in a large observational cohort of high risk ER positive breast DCIS.

    PubMed

    Guerrieri-Gonzaga, Aliana; Sestak, Ivana; Lazzeroni, Matteo; Serrano, Davide; Rotmensz, Nicole; Cazzaniga, Massimiliano; Varricchio, Clara; Pruneri, Giancarlo; Leonardi, Maria Cristina; Orecchia, Roberto; Galimberti, Viviana; Bonanni, Bernardo; DeCensi, Andrea

    2016-11-01

    Low-dose tamoxifen has comparable antiproliferative effect to the standard dose of 20 mg/day in biomarker trials, but its clinical efficacy remains unclear. We assessed the effect of low-dose tamoxifen on ipsilateral recurrence in ductal carcinoma in situ (DCIS) patients treated in a referral Institution between 1996 and 2008. Following conserving surgery, women received radiotherapy and/or low-dose tamoxifen upon clinical judgment and patient preferences. Cox regression analyses were used with and without confounding factors. Among 1,091 women with DCIS and median age 53 years (IQR: 46-62), 544 (49.9%) received radiotherapy. Of the 833 women with oestrogen receptor (ER) positive DCIS, 467 (56.1%) received low-dose tamoxifen. After a median of 7.7 years, 235 ipsilateral recurrences and 62 contralateral breast tumors were observed. Low-dose tamoxifen significantly decreased any breast event (HR = 0.70, 95% CI: 0.54-0.91) and ipsilateral DCIS recurrence (HR = 0.66, 95% CI: 0.49-0.88), but not ipsilateral invasive recurrence or contralateral tumors. Radiotherapy showed a large significant reduction for any breast event (HR = 0.55, 95% CI: 0.42-0.72). Tamoxifen was more effective on all breast events in women aged >50 years than in women aged ≤50 (HR = 0.51, 95% CI: 0.33-0.77 versus HR = 0.84, 95% CI: 0.60-1.18, p-interaction = 0.03). Age ≤50 years, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase of endometrial cancers and fewer deaths (p = 0.015) were observed on tamoxifen. Low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence in ER positive DCIS in women aged >50 years. A randomized trial is underway to confirm these findings. PMID:27381855

  20. Five years of stable disease with maintenance therapy using bevacizumab and tamoxifen in a patient with metastatic breast cancer

    PubMed Central

    Roviello, Giandomenico; Francini, Edoardo; Perrella, Armando; Laera, Letizia; Mazzei, Maria Antonietta; Guerrini, Susanna; Roviello, Franco; Marrelli, Daniele; Petrioli, Roberto

    2015-01-01

    Bevacizumab and Tamoxifen are valid therapeutic options for metastatic breast cancer (mBC) patients. In this report, we describe a 47 year old woman with mBC successfully treated with a maintenance therapy with Bevacizumab+Tamoxifen. A maintenance approach using 2 different drugs with different targets and mechanism of action, such as anti-angiogenic and anti-hormonal treatment is particularly intriguing because they affect different pathways involved in mBC progression. Further studies including a large number of patients are needed, in order to select women who could benefit from this maintenance approach. PMID:25719413

  1. Estrogen and progesterone receptor expression of decidual endometrium in a postmenopausal woman treated with tamoxifen and megestrol acetate.

    PubMed

    Cohen, I; Shulman, A; Altaras, M; Tepper, R; Cordoba, M; Beyth, Y

    1994-01-01

    To the best of our knowledge, this is the first report of in vivo endometrial estrogen and progesterone receptor induction as a result of tamoxifen exposure in a postmenopausal breast cancer patient. The following observations, that the postmenopausal endometrium is sensitive to tamoxifen, that this agent can act as an estrogen-like substance, and that it may cause proliferation of the endometrium in the absence of progestin, may explain the endometrial decidual changes described herein as a protective mechanism against possible neoplastic endometrial changes. PMID:7959340

  2. High-dose methotrexate with leucovorin rescue, vinblastine, and bleomycin with or without tamoxifen in metastatic renal cell carcinoma.

    PubMed

    Bell, D R; Aroney, R S; Fisher, R J; Levi, J A

    1984-04-01

    A regimen of high-dose methotrexate with leucovorin rescue, vinblastine, and bleomycin with or without tamoxifen was administered to 34 patients with metastatic renal cell carcinoma. No complete remissions were observed, but ten patients (30%) achieved partial remission and an additional 13 patients (39%) had stabilization of disease. The median survival of responding patients (110 weeks) was significantly longer than that of nonresponding patients. The addition of tamoxifen did not influence response or survival. This regimen was tolerated without significant toxicity. A prospective randomized study of the vinblastine and high-dose methotrexate regimen compared to the respective single agents seem to be indicated. PMID:6201268

  3. Five years of stable disease with maintenance therapy using bevacizumab and tamoxifen in a patient with metastatic breast cancer.

    PubMed

    Roviello, Giandomenico; Francini, Edoardo; Perrella, Armando; Laera, Letizia; Mazzei, Maria Antonietta; Guerrini, Susanna; Roviello, Franco; Marrelli, Daniele; Petrioli, Roberto

    2015-01-01

    Bevacizumab and Tamoxifen are valid therapeutic options for metastatic breast cancer (mBC) patients. In this report, we describe a 47 year old woman with mBC successfully treated with a maintenance therapy with Bevacizumab+Tamoxifen. A maintenance approach using 2 different drugs with different targets and mechanism of action, such as anti-angiogenic and anti-hormonal treatment is particularly intriguing because they affect different pathways involved in mBC progression. Further studies including a large number of patients are needed, in order to select women who could benefit from this maintenance approach. PMID:25719413

  4. 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. PMID:25411473

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

    PubMed

    Shimizu, Chikako; Watanabe, Toru

    2002-12-01

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

  6. Modern Vaccines/Adjuvants Formulation—Session 2 (Plenary II)

    PubMed Central

    Collin, Nicolas

    2013-01-01

    On the 15–17th May 2013, the Fourth International Conference on Modern Vaccines/Adjuvants Formulation was organized in Lausanne, Switzerland, and gathered stakeholders from academics and from the industry to discuss several challenges, advances and promises in the field of vaccine adjuvants. Plenary session 2 of the meeting was composed of four different presentations covering: (1) the recent set-up of an adjuvant technology transfer and training platform in Switzerland, (2) the proposition to revisit existing paradigms of modern vaccinology, (3) the properties of polyethyleneimine as potential new vaccine adjuvant, and (4) the progresses in the design of HIV vaccine candidates able to induce broadly neutralizing antibodies. PMID:23966098

  7. 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

  8. [A case of non-small cell lung cancer with hemodialysis which responded to docetaxel monotherapy].

    PubMed

    Abe, Yumiko; Tanaka, Kentaro; Matsumoto, Koichiro; Takayama, Koichi; Inoue, Hiroyuki; Izumi, Miiru; Inoue, Hiromasa; Nakanishi, Yoichi

    2010-10-01

    A 56-year-old man receiving hemodialysis treatment was hospitalized for examination of a mass in the right middle lobe. Chest computed tomography showed a right hilar mass shadow accompanied by pleural effusion. Non-small cell lung cancer (NSCLC) was diagnosed by cytological examination of the pleural effusion. No epidermal growth factor receptor (EGFR) mutation was found. He was treated with 6 courses of docetaxel as first-line chemotherapy. Docetaxel was administered on the same day as hemodialysis. Adverse events, including hematotoxicity, were managed safely and no delay in administration occurred. This chemotherapy resulted in a partial response. Because docetaxel is metabolized in the liver and does not affect renal function, it can be administered as a standard regimen. This suggests that docetaxel monotherapy is an efficient therapy for non-small cell lung cancer patients receiving hemodialysis. PMID:21066867

  9. Total and free valproic acid: plasma level/dose ratio in monotherapy.

    PubMed

    Abadín, J A; Durán, J A; Sánchez, A; Serrano, J S

    1991-04-01

    Free plasma level/dose ratio of valproic acid (L/D-F) can be more effective than total plasma level/dose ratio (L/D-T) in adjusting dosage regimens. The influence of age, dose, and plasma concentration have been studied on L/D-T and L/D-F ratios. L/D-T and L/D-F ratios from 67 outpatients under long-term monotherapy were obtained. Analytical data was carried out by fluorescent polarized immunoassay. L/D-T and L/D-F ratios do not vary according to age. L/D-T and L/D-F ratios decreased while the dosage increased; both ratios increased with an increase in total plasma level of valproic acid. Significant differences were found between L/D-T and L/D-F ratios. Dose and interindividual variations are the factors which most influence L/D ratios of valproic acid. PMID:2051846

  10. 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

  11. 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…

  12. An Open-Label Study of Lamotrigine Adjunct or Monotherapy for the Treatment of Adolescents with Bipolar Depression

    ERIC Educational Resources Information Center

    Chang, Kiki; Saxena, Kirti; Howe, Meghan

    2006-01-01

    Objective: The treatment of pediatric bipolar depression has not been well studied. The authors wished to prospectively study the efficacy of lamotrigine as adjunctive or monotherapy in adolescents with bipolar disorder who were experiencing a depressive episode. Method: This was an 8-week open-label trial of lamotrigine with 20 adolescents ages…

  13. 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

  14. 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

  15. A Meta-analysis of Sequential Intravenous/Oral Moxifloxacin Monotherapy for Treatment of Skin and Skin Structure Infections.

    PubMed

    Chu, Y; Qu, J; Qu, L-Y; Luo, Y-F; Jiang, M-Y

    2015-12-01

    Moxifloxacin is widely recognized for the treatment of bacterial infections of the respiratory tract such as community acquired pneumonia, acute bacterial sinusitis and acute exacerbations of chronic bronchitis. However, the use of moxifloxacin for skin infections is much valued in recent years. This study is to compare the clinical efficacy and safety of moxifloxacin monotherapy among adults with skin and skin structure infections. The meta-analysis of RCTs is conducted by searching Medline, Embase, Pubmed and the Cochrane Library. 6 RCTs, involving a total of 2608 patients, were included in the meta-analysis. English and Chinese language papers were reviewed. The results of the meta-analysis showed that the moxifloxacin monotherapy has similar clinical cure rate, bacteriological success rates and mortality compared with the control group. The drug-related adverse of moxifloxacin was significantly higher than that in the control group, although the overall incidence of adverse events, serious adverse events, and serious drug-related adverse events were similar between the compared treatment groups. Through this meta-analysis, we can draw a conclusion that moxifloxacin monotherapy has similar effectiveness and relative safety as other recommended antibiotics for the treatment of SSSIs. At the same time, it possesses the superior bacteria eradication rate. The once-daily dosing of moxifloxacin monotherapy may be a useful alternative for other recommended antibiotic therapy. PMID:26070015

  16. 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

  17. 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

  18. Fractional CO2 Laser Resurfacing as Monotherapy in the Treatment of Atrophic Facial Acne Scars

    PubMed Central

    Majid, Imran; Imran, Saher

    2014-01-01

    Background: While laser resurfacing remains the most effective treatment option for atrophic acne scars, the high incidence of post-treatment adverse effects limits its use. Fractional laser photothermolysis attempts to overcome these limitations of laser resurfacing by creating microscopic zones of injury to the dermis with skip areas in between. Aim: The aim of the present study is to assess the efficacy and safety of fractional CO2 laser resurfacing in atrophic facial acne scars. Materials and Methods: Sixty patients with moderate to severe atrophic facial acne scars were treated with 3-4 sessions of fractional CO2 laser resurfacing at 6-week intervals. The therapeutic response to treatment was assessed at each follow up visit and then finally 6 months after the last laser session using a quartile grading scale. Response to treatment was labelled as ‘excellent’ if there was >50% improvement in scar appearance and texture of skin on the grading scale while 25-50% response and <25% improvement were labelled as ‘good’ and ‘poor’ response, respectively. The overall satisfaction of the patients and any adverse reactions to the treatment were also noted. Results: Most of the patients showed a combination of different morphological types of acne scars. At the time of final assessment 6 months after the last laser session, an excellent response was observed in 26 patients (43.3%) while 15 (25%) and 19 patients (31.7%) demonstrated a good and poor response respectively. Rolling and superficial boxcar scars responded the best while pitted scars responded the least to fractional laser monotherapy. The commonest reported adverse effect was transient erythema and crusting lasting for an average of 3-4 and 4-6 days, respectively while three patients developed post-inflammatory pigmentation lasting for 8-12 weeks. Conclusions: Fractional laser resurfacing as monotherapy is effective in treating acne scars especially rolling and superficial boxcar scars with minimal

  19. 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

  20. Increased Beta Frequency (15-30 Hz) Oscillatory Responses in Euthymic Bipolar Patients Under Lithium Monotherapy.

    PubMed

    Tan, Devran; Özerdem, Ayşegül; Güntekin, Bahar; Atagün, M Ilhan; Tülay, Elif; Karadağ, Figen; Başar, Erol

    2016-04-01

    The effect of lithium on neurocognition is not still fully explored. Brain oscillatory activity is altered in bipolar disorder. We aimed to assess the oscillatory responses of euthymic bipolar patients and how they are affected by lithium monotherapy. Event-related oscillations in response to visual target stimulus during an oddball paradigm in 16 euthymic drug-free and 13 euthymic lithium-treated bipolar patients were compared with 16 healthy controls. The maximum peak-to-peak amplitudes were measured for each subject's averaged beta (15-30 Hz) responses in the 0- to 300-ms time window over frontal (F3, Fz, F4), central (C3, Cz, C4), temporal (T7, T8), temporo-parietal (TP7, TP8), parietal (P3, Pz, P4), and occipital (O1, Oz, O2) areas. Patients under lithium monotherapy had significantly higher beta responses to visual target stimuli than healthy controls (P=.017) and drug-free patients (P=.015). The increase in beta response was observed at all electrode locations, however, the difference was statistically significant for the left (T7; P=.016) and right (T8; P=.031) temporal beta responses. Increased beta responses in drug-free patients and further significant increase in lithium-treated patients may be indicative of a core pathophysiological process of bipolar disorder and how it is affected by lithium. Whether the finding corresponds to lithium's corrective effect on the underlying pathology or to its neurocognitive side effect remains to be further explored. In either case, the finding is a sign that the oscillatory activity may be useful in tracking medication effect in bipolar disorder. PMID:25465436

  1. Opioid and adjuvant analgesics: compared and contrasted.

    PubMed

    Khan, Mohammed Ilyas Ahmed; Walsh, Declan; Brito-Dellan, Norman

    2011-08-01

    An adjuvant (or co-analgesic) is a drug that in its pharmacological characteristic is not necessarily primarily identified as an analgesic in nature but that has been found in clinical practice to have either an independent analgesic effect or additive analgesic properties when used with opioids. The therapeutic role of adjuvant analgesics (AAs) is to increase the therapeutic index of opioids by a dose-sparing effect, add a unique analgesic action in opioid-resistant pain, or reduce opioid side effects. A notable difference between opioids and AAs is that unlike opioids some AAs are associated with permanent organ toxicity, for example, nonsteroidal anti-inflammatory drugs (NSAIDs) and renal failure. It is impossible to predict in advance in a given individual what opioid dose they may require to control cancer pain. Most AAs have a ceiling effect for their analgesic actions, but often with continued dose-related toxicities and side effects (with the exception of glucocorticoids). The blood levels of opioids (and their metabolites) can be measured with great precision and accuracy. There is sometimes a role for drug blood levels of certain AAs, like tricyclic antidepressants or anticonvulsants when used for neuropathic pain. Age affects metabolism of most opioids. The therapeutic window of opioids is wide, with no ceiling effect. Most AAs (except corticosteroids) have a narrow therapeutic window. Naloxone is a pure opioid antagonist that competes and displaces opioids from their receptor sites. All clinically useful opioids are mu opioid receptor agonists. Not all routes of administration are available to all opioids. Adjuvant analgesics lack the versatility in routes of administration that opioids possess. Dosing flexibility is a major advantage when treating cancer-related pain with opioids. Dose flexibility is much less with AAs than opioids. Unlike opioids, the analgesic response is usually observed within hours to days of attaining an adequate dose with most

  2. [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

  3. Adjuvant Immunotherapy of Melanoma, and Development of New Approaches Using the Neo- Adjuvant Approach in Melanoma

    PubMed Central

    Davar, Diwakar; Tarhini, Ahmad

    2013-01-01

    Melanoma is the third most common skin cancer but the leading cause of death from cutaneous malignancies. While early-stage disease is frequently cured by surgical resection with excellent long-term survival, patients with deeper primary lesions (AJCC stage IIB-C) and those with microscopic (IIIA) or clinically evident regional lymph node or in-transit metastases (IIIB-C) have an increased risk of relapse and death–the latter approaching 70% or more at 5 years. In patients at high-risk of recurrence/metastases, adjuvant therapy with high-dose interferon alpha-2b (HDI) following definitive surgical resection has been shown to improve relapse free and overall survival. Neo-adjuvant chemotherapy and/or radiotherapy have offered the prospect to improve regional recurrence risk and overall survival in several solid tumors. The advent of effective new molecularly targeted therapies for metastatic disease and new immunotherapies that overcome checkpoints of immune response have augmented the range of new options that are in current trial evaluation to determine their role as potential adjuvant therapies, alone and in combination with one another, and the established modality of IFNα. The differential characteristics of the host immune response between early and advanced melanoma provide a strong mechanistic rationale for the use of neo-adjuvant immunotherapeutic approaches in melanoma, and the opportunity to evaluate the mechanism of action suggest neoadjuvant trial evaluation for each of the new candidate agents and combinations of interest. Several neo-adjuvant trials have been conducted in the phase II setting, which have illuminated the mechanism of IFNα, as well as providing insight to the effects of anti-CTLA4 blocking antibodies. These agents (anti-CTLA4 blocking antibody ipilimumab [BMS], and BRAF inhibitor vemurafenib [Genentech]) are likely to be followed by other immunotherapies that may overcome the PD-1 checkpoint (anti-PD1 [BMS, Merck, Curetech] and anti

  4. 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

  5. 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

  6. Comparison of tenofovir plus lamivudine versus tenofovir monotherapy in patients with lamivudine-resistant chronic hepatitis B

    PubMed Central

    Park, Chan Ho; Jung, Seok Won; Shin, Jung Woo; Bae, Mi Ae; Lee, Yoon Im; Park, Yong Tae; Chung, Hwa Sik; Park, Neung Hwa

    2016-01-01

    Background/Aims: Tenofovir disoproxil fumarate (TDF) exhibits similar antiviral efficacy against treatment-naïve and lamivudine (LAM)-resistant chronic hepatitis B (CHB). However, there are few clinical reports on the antiviral effects of TDF–LAM combination therapy compared to TDF monotherapy in patients with LAM-resistant CHB. Methods: We investigated the antiviral efficacy of TDF monotherapy vs. TDF–LAM combination therapy in 103 patients with LAM-resistant CHB. Results: The study subjects were treated with TDF alone (n=40) or TDF–LAM combination therapy (n=63) for ≥6 months. The patients had previously been treated with TDF-based rescue therapy for a median of 30.0 months (range, 8–36 months). A virologic response (VR) was achieved in 99 patients (96.1%): 95.0% (38/40) of patients in the TDF monotherapy group and 96.8% (61/63) of patients in the TDF–LAM combination therapy group. The VR rates were not significantly different between the TDF monotherapy and TDF–LAM combination therapy groups (88.9 vs. 87.3% at month 12, and 94.4 vs. 93.7% at month 24, log-rank p=0.652). Univariate and multivariate analyses revealed that none of the pretreatment factors were significantly associated with VR. Conclusions: TDF monotherapy was as effective as TDF–LAM combination therapy for maintaining viral suppression in the vast majority of patients with LAM-resistant CHB, which suggests that TDF add-on therapy with LAM is unnecessary. PMID:27044766

  7. 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

  8. 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

  9. Role of endoplasmic reticulum stress induction by the plant toxin, persin, in overcoming resistance to the apoptotic effects of tamoxifen in human breast cancer cells

    PubMed Central

    McCloy, R A; Shelley, E J; Roberts, C G; Boslem, E; Biden, T J; Nicholson, R I; Gee, J M; Sutherland, R L; Musgrove, E A; Burgess, A; Butt, A J

    2013-01-01

    Background: Persin is a plant toxin that displays synergistic cytotoxicity with tamoxifen in human breast cancer cell lines. Here, we examined the ability of persin to circumvent tamoxifen resistance and delineated the intracellular signalling pathways involved. Methods: The induction of apoptosis in tamoxifen-resistant and -sensitive breast cancer cells was measured by flow cytometry following treatment with persin±tamoxifen. Markers of endoplasmic reticulum stress (ERS) were analysed following treatment, and their causal role in mediating persin-induced apoptosis was determined using chemical inhibitors and RNA interference. Results: Cells that were resistant to an apoptotic concentration of tamoxifen maintained an apoptotic response to persin. Persin-induced apoptosis was associated with an increase in markers of ERS, that is, CHOP expression and XBP-1 splicing and was decreased by CHOP siRNA. The CASP-4 inhibitor Z-YVAD-FMK markedly inhibited persin-induced apoptosis in both tamoxifen-sensitive and -resistant cells. Conclusion: The cytotoxic effects of persin are CASP-4 dependent and mediated by CHOP-dependent and -independent ERS signalling cascades. Increased ERS signalling contributes to persin-induced reversal of tamoxifen resistance. PMID:24178758

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

    PubMed

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

    2016-06-14

    Mice with a constitutive or tamoxifen-induced Cre recombinase (Cre) expression are frequently used research tools to allow the conditional deletion of target genes via the Cre-loxP system. Here we analyzed for the first time in a comprehensive and comparative way, whether retinal Cre expression or topical tamoxifen treatment itself would cause structural or functional changes, including changes in the expression profiles of molecular markers, glial reactivity and photoreceptor vulnerability. To this end, we characterized the transgenic α-Cre, Lmop-Cre and the tamoxifen-inducible CAGG-CreER™ mouse lines, all having robust Cre expression in the neuronal retina. In addition, we characterized the effects of topical tamoxifen treatment itself in wildtype mice. We performed morphometric analyses, immunohistochemical staining, in vivo ERG and angiography analyses and realtime RT-PCR analyses. Furthermore, the influence of Cre recombinase or topical tamoxifen exposure on neuronal vulnerability was studied by using light damage as a model for photoreceptor degeneration. Taken together, neither the expression of Cre, nor topical tamoxifen treatment caused detectable changes in retinal structure and function, the expression profiles of investigated molecular markers, glial reactivity and photoreceptor vulnerability. We conclude that the Cre-loxP system and its induction through tamoxifen is a safe and reliable method to delete desired target genes in the neural retina. PMID:27026593

  11. High-dose tamoxifen as an enhancer of etoposide cytotoxicity. Clinical effects and in vitro assessment in p-glycoprotein expressing cell lines.

    PubMed Central

    Stuart, N. S.; Philip, P.; Harris, A. L.; Tonkin, K.; Houlbrook, S.; Kirk, J.; Lien, E. A.; Carmichael, J.

    1992-01-01

    Twenty-six patients with relapsed or drug-resistant cancer were treated with a combination of oral etoposide (300 mg day-1 for 3 days) and high-dose oral tamoxifen as a potential modulator of drug resistance (480 or 720 mg day-1 for 6 days beginning 3 days before etoposide). One patient with relapsed high-grade lymphoma and one with adenocarcinoma of unknown primary site has a partial response. Toxicity consisting of nausea, vomiting and subjective dizziness, unsteadiness of gait and malaise occurred during tamoxifen treatment. Serum levels of tamoxifen averaged 3-3.5 microM on day 4 of all courses of treatment at both 480 and 720 mg day-1. N-desmethyltamoxifen levels were lower than tamoxifen during the first course (2 microM) but increased to equal tamoxifen levels during the second course. Didesmethyltamoxifen levels remained below 1 microM. In vitro, both tamoxifen and the standard modulator of multidrug resistance, verapamil, produced minor enhancement of etoposide cytotoxicity in the MCF-7 wt cell line but produced no enhancement with any other cell line. High, intermittent doses of tamoxifen can be given with acceptable toxicity and produce serum levels that have been shown to modulate drug resistance in vitro. In vitro, however, such levels have no significant effect on etoposide cytotoxicity towards a range of wild-type and MDR cell lines. PMID:1358168

  12. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer.

    PubMed

    Saladores, P; Mürdter, T; Eccles, D; Chowbay, B; Zgheib, N K; Winter, S; Ganchev, B; Eccles, B; Gerty, S; Tfayli, A; Lim, J S L; Yap, Y S; Ng, R C H; Wong, N S; Dent, R; Habbal, M Z; Schaeffeler, E; Eichelbaum, M; Schroth, W; Schwab, M; Brauch, H

    2015-02-01

    Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R(2): 53%, P<10(-77)). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43-0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04-4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS. PMID:25091503

  13. Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer

    PubMed Central

    Saladores, P; Mürdter, T; Eccles, D; Chowbay, B; Zgheib, N K; Winter, S; Ganchev, B; Eccles, B; Gerty, S; Tfayli, A; Lim, J S L; Yap, Y S; Ng, R C H; Wong, N S; Dent, R; Habbal, M Z; Schaeffeler, E; Eichelbaum, M; Schroth, W; Schwab, M; Brauch, H

    2015-01-01

    Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, P<10−77). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS. PMID:25091503

  14. Comparative metabolic study between two selective estrogen receptor modulators, toremifene and tamoxifen, in human liver microsomes.

    PubMed

    Watanabe, Miyuki; Watanabe, Noriko; Maruyama, Sakiko; Kawashiro, Takashi

    2015-10-01

    Toremifene (TOR) and Tamoxifen (TAM) are widely used as endocrine therapy for estrogen receptor positive breast cancer. Poor metabolizers of TAM are likely to have worse clinical outcomes than patients who exhibit normal TAM metabolism due to lower plasma level of its active metabolite, 4-hydroxy-N-desmethyl (4OH-NDM) tamoxifen (endoxifen). In this study, we examined the role of individual cytochrome P450 (CYP) isoforms in the metabolism of TOR to N-desmethyl (NDM), 4-hydroxy (4OH) and 4OH-NDM metabolites in comparison with TAM using human liver microsomes (HLMs) with selective chemical inhibitors for each CYP isoform and recombinant CYP proteins. Similar levels of NDM metabolites were formed for both TOR and TAM, and N-demethylation of both compounds was primarily carried out by CYP3A4. We found that the formation of 4OH-NDM-TOR was catalyzed both by CYP2C9 and CYP2D6, whereas the formation of 4OH-TAM and endoxifen was specifically catalyzed by CYP2D6 in HLMs. Our results suggest that the potential contribution of CYP2D6 in the bioactivation pathway of TOR may be lower compared to TAM, and may have a different impact on clinical outcome than CYP2D6 polymorphisms. PMID:26423799

  15. Structure-Activity Relationships for the Antifungal Activity of Selective Estrogen Receptor Antagonists Related to Tamoxifen

    PubMed Central

    Butts, Arielle; Martin, Jennifer A.; DiDone, Louis; Bradley, Erin K.; Mutz, Mitchell; Krysan, Damian J.

    2015-01-01

    Cryptococcosis is one of the most important invasive fungal infections and is a significant contributor to the mortality associated with HIV/AIDS. As part of our program to repurpose molecules related to the selective estrogen receptor modulator (SERM) tamoxifen as anti-cryptococcal agents, we have explored the structure-activity relationships of a set of structurally diverse SERMs and tamoxifen derivatives. Our data provide the first insights into the structural requirements for the antifungal activity of this scaffold. Three key molecular characteristics affecting anti-cryptococcal activity emerged from our studies: 1) the presence of an alkylamino group tethered to one of the aromatic rings of the triphenylethylene core; 2) an appropriately sized aliphatic substituent at the 2 position of the ethylene moiety; and 3) electronegative substituents on the aromatic rings modestly improved activity. Using a cell-based assay of calmodulin antagonism, we found that the anti-cryptococcal activity of the scaffold correlates with calmodulin inhibition. Finally, we developed a homology model of C. neoformans calmodulin and used it to rationalize the structural basis for the activity of these molecules. Taken together, these data and models provide a basis for the further optimization of this promising anti-cryptococcal scaffold. PMID:26016941

  16. 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