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Although Tamoxifen (TAM) is one of the most widely used drugs in managing breast cancer, many women still relapse after long-term therapy. Caffeic acid phenethyl ester (CAPE) is a polyphenolic compound present in many medicinal plants and in propolis. The present study examined the effect of CAPE on TAM cytotoxicity in MCF-7 cells. MCF-7 cells were treated with different concentrations of TAM and/or CAPE for 48 h. This novel combination exerted synergistic cytotoxic effects against MCF-7 cells via induction of apoptotic machinery with activation of caspases and DNA fragmentation, along with downregulation of Bcl-2 and Beclin 1 expression levels. However, the mammalian microtubule-associated protein light chain LC 3-II level was unchanged. Vascular endothelial growth factor level was also decreased, whereas levels of glutathione and nitric oxide were increased. In conclusion, CAPE augmented TAM cytotoxicity via multiple mechanisms, providing a novel therapeutic approach for breast cancer treatment that can overcome resistance and lower toxicity. This effect provides a rationale for further investigation of this combination.
The results of this study indicate that the RS assay impacts medical oncologist adjuvant treatment recommendations, patient treatment choice, and patient anxiety.
The involvement of tissue ischemia in obesity-induced kidney injury remains to be elucidated. Compared with low fat diet (LFD)-mice, high fat diet (HFD)-fed mice became obese with tubular enlargement, glomerulomegaly and peritubular capillary rarefaction, and exhibited both tubular and glomerular damages. In HFD-fed mice, despite the increase in renal pimonidazole-positive areas, the expressions of the hypoxia-responsive genes such as Prolyl-hydroxylase PHD2, a dominant oxygen sensor, and VEGFA were unchanged indicating impaired hypoxic response. Tamoxifen inducible proximal tubules (PT)-specific Phd2 knockout (Phd2-cKO) mice and their littermate control mice (Control) were created and fed HFD or LFD. Control mice on HFD (Control HFD) exhibited renal damages and renal ischemia with impaired hypoxic response compared with those on LFD. After tamoxifen treatment, HFD-fed knockout mice (Phd2-cKO HFD) had increased peritubular capillaries and the increased expressions of hypoxia responsive genes compared to Control HFD mice. Phd2-cKO HFD also exhibited the mitigation of tubular damages, albuminuria and glomerulomegaly. In human PT cells, the increased expressions of hypoxia-inducible genes in hypoxic condition were attenuated by free fatty acids. Thus, aberrant hypoxic responses due to dysfunction of PHD2 caused both glomerular and tubular damages in HFD-induced obese mice. Phd2-inactivation provides a novel strategy against obesity-induced kidney injury.
Toremifene significantly decreased the incidence of new vertebral fractures in men receiving androgen deprivation therapy for prostate cancer. It also significantly improved bone mineral density, bone turnover markers and serum lipid profiles.
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We present a scalable synthesis of a versatile MTX reagent with an azide ligation handle that allows rapid γ-selective conjugation to yield MTX fusion compounds (MFCs) appropriate for MASPIT, a three-hybrid system that enables the identification of mammalian cytosolic proteins that interact with a small molecule of interest. We selected three structurally diverse pharmacologically active compounds (tamoxifen, reversine, and FK506) as model baits. After acetylene functionalization of these baits, MFCs were synthesized via a CuAAC reaction, demonstrating the general applicability of the MTX reagent. In analytical mode, MASPIT was able to give concentration-dependent reporter signals for the established target proteins. Furthermore, we demonstrate that the sensitivity obtained with the new MTX reagent was significantly stronger than that of a previously used non-regiomeric conjugate mixture. Finally, the FK506 MFC was explored in a cellular array screen for targets of FK506. Out of a pilot collection of nearly 2000 full-length human ORF preys, FKBP12, the established target of FK506, emerged as the prey protein that gave the highest increase in luciferase activity. This indicates that our newly developed synthetic strategy for the straightforward generation of MFCs is a promising asset to uncover new intracellular targets using MASPIT cellular array screening.
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.
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The effects of tamoxifen and soy on apoptosis of the hippocampus and dentate gyrus of ovariectomized rats after repeated seizures were investigated. Female rats were divided into: (1) Control, (2) Sham, (3) Sham-Tamoxifen (Sham-T), (4) Ovariectomized (OVX), (5) OVX-Tamoxifen (OVX-T), (6)OVX-Soy(OVX-S) and (7) OVX-S-T. The animals in the OVX-S, OVX-T and OVX-S-T groups received soy extract (60 mg/kg; i.p.), tamoxifen (10 mg/kg) or both for 2 weeks before induction of seizures. The animals in these groups additionally received the mentioned treatments before each injection of pentylenetetrazole (PTZ; 40 mg/kg) for 6 days. The animals in the Sham and OVX groups received a vehicle of tamoxifen and soy. A significant decrease in the seizure score and TUNEL-positive neurons was seen in the OVX group compared to the Sham (P < 0.001). The animals in both the OVX-T and OVX-S groups had a significantly higher seizure score as well as number of TUNEL-positive neurons compared to the OVX group (P < 0.01-P < 0.001). Co-treatment of the OVX rats by the extract and tamoxifen decreased the seizure score and number of TUNEL-positive neurons compared to OVX-S (P < 0.001). Treatment of the OVX rats by either soy or tamoxifen increased the seizure score as well as the number of TUNEL-positive neurons in the hippocampal formation. Co-administration of tamoxifen and soy extract inhibited the effects of the soy extract and tamoxifen when they were administered alone. It might be suggested that both soy and tamoxifen have agonistic effects on estrogen receptors by changing the seizure severity.
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Tamoxifen and aromatase inhibitor therapy affect VEGF and endostatin levels and likely contribute to the angiogenic balance in breast cancer patients. Aspirin decreased the proangiogenic effects of tamoxifen, suggesting that antiplatelet and/or antiangiogenic therapy might improve the effectiveness of tamoxifen in women with breast cancer.
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Patients with estrogen receptor-positive (ER+) breast cancers are often treated with aromatase inhibitors or by antiestrogens such as tamoxifen to prevent disease recurrence. Resistant tumors nevertheless develop and it is commonly assumed that they arise by the induction of mutations. However, it is also possible that resistant tumors grow from preexisting variant populations within the original tumor. We have investigated this possibility in the case of the MCF-7 breast cancer cell line. The line was cultured for a prolonged period either in the presence of tamoxifen to block the action of oestrogen or in the absence of estrogen to mimic the action of oophorectomy or treatment with aromatase inhibitors. Both treatments led to growth inhibition followed by eventual outgrowth of sub-lines. Five of these sub-lines were developed and characterized for sensitivity to tamoxifen and to the antibiotic rapamycin, expression of HE R2 and PAX2, and phosphorylation of Akt, p70S6K, 4E-BP1, rpS6, EGFR1, Erk and HE R2. All six lines were ER+ and could be divided into four phenotypes distinguished by cell volume, DNA content (ploidy) and cell cycle time. In two cases, selection with tamoxifen and selection in the absence of estrogen produced similar phenotypes. Rapamycin resistance was a feature of the sub-lines developed under estrogen deprivation and was associated with loss of active phospho-HE R2 and acquisition of PAX2 expression. The results support the conclusion that the MCF-7 cell line is heterogeneous and that the selection conditions allow the growth of pre-existing phenotypes.
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Postsurgical treatment of ductal intraepithelial neoplasia (DIN) with standard doses of tamoxifen has not reached a consensus yet. Given positive results of low-dose tamoxifen on breast cancer biomarkers modulation, we analyzed a large cohort of DIN patients treated with low-dose tamoxifen or no treatment as per institutional guidelines.
The Mammostrat score predicts DRFS for patients treated with exemestane and patients treated with tamoxifen followed by exemestane irrespective of nodal status and chemotherapy. The ability of this test to provide additional outcome data after treatment provides additional evidence of its use in risk stratification of ER-positive postmenopausal patients with breast cancer.
We determined total Purkinje cell (PC) numbers in cerebella of wild-type (+/+) and heterozygous (rl/+) reeler mice of either sex during early postnatal development; in parallel, we quantified levels of neuroactive steroids in the cerebellum with mass spectrometry. We also quantified reelin mRNA and protein expression with RT-PCR and Western blotting. PC numbers are selectively reduced at postnatal day 15 (P15) in rl/+ males in comparison to +/+ males, +/+ females, and rl/+ females. Administration of 17beta-estradiol (17beta-E) into the cisterna magna at P5 increases PC numbers in rl/+ males, but not in the other groups; conversely, estrogen antagonists 4-OH-tamoxifen or ICI 182,780 reduce PC numbers in +/+ and rl/+ females, but have no effect in males. Testosterone (T) levels at P5 are much higher in males than in females, reflecting the perinatal testosterone surge in males. In addition, rl/+ male cerebella at P5 show a peculiar hormonal profile in comparison with the other groups, consisting of increased levels of T and 17beta-E, and decreased levels of dihydrotestosterone. RT-PCR analysis indicated that heterozygosity leads to a 50% reduction of reelin mRNA in the cerebellum in both sexes, as expected, and that 17beta-E upregulates reelin mRNA, particularly in rl/+ males; reelin mRNA upregulation is associated with an increase of all major reelin isoforms. These effects may represent a novel model of how reelin deficiency interacts with variable perinatal levels of neuroactive steroids, leading to gender-dependent differences in genetic vulnerability.
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Between December 2006 and December 2008, 114 patients were recruited (age 55.3±7.7 years). The duration and dose of prednisolone received was 62.2±64 months and 6.7±5.9 mg/day, respectively. Baseline vertebral fracture was present in six (5%) patients. In all, 57 patients were allocated to each of the treatment arms. Demographic data, osteoporotic risk factors and BMD at various sites were similar between the two groups of patients. At month 12, a significant gain in the lumbar spine (+1.3±0.4%; p=0.004) and total hip BMD (+1.0±0.4%; p=0.01) was observed in patients treated with raloxifene but a significant decrease in BMD of the lumbar spine (-0.9±0.4%; p=0.045) and hip (-0.8±0.3%; p=0.01) occurred in the placebo group. The femoral neck BMD did not change significantly in favour of raloxifene. Three new fractures developed exclusively in the patients treated with placebo. Bone formation (serum osteocalcin and procollagen type I N-terminal) and resorption (urine deoxypyridinoline and type I collagen) markers decreased significantly in the raloxifene group but not in patients treated with placebo. Leg cramps were numerically more frequent in the raloxifene group (7% vs 0%) but thromboembolism was not reported in any patients.
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A meta-analysis of randomized trials was performed to compare the efficacy of toremifene (TOR) with tamoxifen (TAM) in patients with breast cancer. A total of 4,768 intention-to-treat patients from nine randomized trials were identified, with 2,587 patients in TOR group and 2,181 patients in TAM group. The primary outcomes were objective response rate (ORR), time to progression (TTP), and overall survival (OS). The ORR for TOR group was 26.2 % (303/1,156), whereas the ORR for TAM group was 25.2 % (284/1,128). The pooled RR suggested that the ORR were not statistically different between the two therapeutic groups (RR 1.04, 95 % CI 0.91-1.20, P = 0.57). The median TTP was 6.7 months for the TOR group and 9.7 months for the TAM group. The median OS was 30.1 months for the TOR group and 31.7 months for the TAM group. There were no significant difference in TTP and OS between two therapeutic groups (for TTP: HR 0.91, 95 % CI 0.82-1.00; for OS: HR 1.02, 95 % CI 0.91-1.15). Adverse events were generally similar in two therapeutic groups, but TOR may cause fewer vaginal bleeding (4.0 vs. 6.7 %, P < 0.01), headache (0.2 vs. 3.1 %, P = 0.02) and thromboembolic events (4.7 vs. 7.0 %, P = 0.04). Sensitivity analyses were performed by deleting a single study each time; all the results were not materially altered. In summary, the results of this meta-analysis suggest that TOR and TAM have similar efficacy in the treatment of patients with breast cancer.
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Infertile women undergoing ovulation induction (OI) with clomiphene citrate (CC) who have adequate follicular recruitment and an endometrial thickness of <7 mm as determined by transvaginal sonography in the late follicular phase were switched to tamoxifen for OI in a subsequent cycle. A comparison between the endometrial thickness on CC and tamoxifen was made with by paired analysis. For women undergoing OI with CC who have adequate follicular recruitment and thin endometrium (<7 mm), switching to tamoxifen in subsequent cycles improves endometrial thickness.
Acquired tamoxifen resistance develops in the majority of hormone-responsive breast cancers and frequently involves overexpression of the PI3K/AKT axis. Here, breast cancer cells with elevated endogenous AKT or overexpression of activated AKT exhibited tamoxifen-stimulated cell proliferation and enhanced cell motility. To gain mechanistic insight on AKT-induced endocrine resistance, gene expression profiling was performed to determine the transcripts that are differentially expressed post-tamoxifen therapy under conditions of AKT overexpression. Consistent with the biologic outcome, many of these transcripts function in cell proliferation and cell motility networks and were quantitatively validated in a larger panel of breast cancer cells. Moreover, ribonucleotide reductase M2 (RRM2) was revealed as a key contributor to AKT-induced tamoxifen resistance. Inhibition of RRM2 by RNA interference (RNAi)-mediated approaches significantly reversed the tamoxifen-resistant cell growth, inhibited cell motility, and activated DNA damage and proapoptotic pathways. In addition, treatment of tamoxifen-resistant breast cancer cells with the small molecule RRM inhibitor didox significantly reduced in vitro and in vivo growth. Thus, AKT-expressing breast cancer cells upregulate RRM2 expression, leading to increased DNA repair and protection from tamoxifen-induced apoptosis.
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Ospemifene is a selective estrogen receptor modulator (SERM) approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy (VVA) due to menopause. As the first non-hormonal treatment for this indication, the approval of ospemifene represents a significant milestone in postmenopausal women's health. Ospemifene is a triphenylethylene similar in chemical structure to tamoxifen and toremifene. Consistent with other SERMs such as tamoxifen, toremifene, and raloxifene, ospemifene possesses a distinctive mix of estrogenic and antiestrogenic tissue-specific effects in bone, breast tissue, serum lipids, and the vagina. Among the approved SERMs, ospemifene is the only agent with a nearly full estrogen agonist effect on the vaginal epithelium while having neutral to slight estrogenic effects in the endometrium, making ospemifene uniquely suited for the treatment of dyspareunia associated with VVA, also known as atrophic vaginitis, which affects up to 50% of postmenopausal women. This review begins with a brief history of the discovery of ospemifene, its mechanism of action, and its preclinical development, with an emphasis on its tissue-specific effects on bone, breast, uterus and endometrium, serum lipids and vagina. A brief discussion on the genotoxicity of ospemifene compared to tamoxifen and toremifene is included. The focus then shifts to the clinical development of ospemifene from Phase I through Phase III. We will close with the FDA approval of ospemifene and a justification of the future clinical evaluation of ospemifene as a potential breast cancer chemopreventive agent, where several preclinical studies in different rodent breast cancer models strongly suggest ospemifene is as effective as tamoxifen.
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Loss of cyclin-dependent kinase (CDK) 10 expression may be an important mechanism of tamoxifen resistance and the 5' CpG island associated with the CDK10 gene has been suggested to be a target for aberrant methylation in breast cancer.
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Epidemiological research has indicated that the anti-oestrogen tamoxifen, used in breast cancer therapy, may increase the risk of gastric adenocarcinoma of the intestinal but not of the diffuse type. To test this hypothesis, and evaluate possible involvement of oestrogen receptors (ERs), we conducted a study amongst tamoxifen users and non-users. The study participants comprised women in the county of Stockholm who in the Swedish Cancer Register were first recorded with breast cancer and subsequently gastric cancer during the period January 1958-August 2005. Medical records were scrutinised to verify the diagnoses and classify into use or non-use of tamoxifen. Tumour material was reviewed histologically to verify gastric adenocarcinoma diagnosis and classify these cancers into intestinal or diffuse type. Intestinal adenocarcinomas were analysed immunohistochemically for the presence of ER alpha, beta and beta cx. Amongst 68 women with verified gastric adenocarcinoma, 30 had been treated with tamoxifen and 38 not. The intestinal type of gastric adenocarcinoma was not more frequent amongst tamoxifen users (27%) than amongst non-users (34%) (p=0.601). There were no material differences between the tamoxifen groups regarding distribution of any of the three ERs of the intestinal adenocarcinoma specimens. Tamoxifen users had a shorter latency between breast cancer and gastric adenocarcinoma (4 versus 13 years) which was similar in the intestinal and diffuse types. This study does not support the hypothesis that tamoxifen increases the isolated risk of the intestinal type, but it indicates that tamoxifen use might accelerate the tumour progression or increase the overall risk of gastric adenocarcinoma.
Women with the highest IR-HOMA scores were associated with a significantly higher weight, body mass index, waist and waist-to-hip ratio (p < 0.05). Raloxifene significantly reduced the IR-HOMA scores from 5.76 ± 2.91 to 1.93 ± 0.96 (p = 0.02) and modified the lipid profile in insulin-resistant patients when compared with the placebo group and those patients receiving raloxifene in the insulin-sensitive group.
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Our Hereditary Cancer Registry was searched for gynecologic and peritoneal cancers linked to mutations in BRCA1 or BRCA2. Invasive cancers were registered in 101 mutation carriers with complete pathology reports. Efforts were made to secure diagnostic surgical pathology tissues for review. All records and available diagnostic slides were meticulously studied, and primary cancers were classified.
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Prevention of osteopenia/osteoporosis in postmenopausal patients can reduce fracture risk. In this view, the use of Selective Estrogen Receptor Modulators (SERMs) appear to be important in managing this condition. Bazedoxifene Acetate (BZA) is a third-generation SERM that showed to protect bone mass in postmenopausal women with osteopenia, and to reduce vertebral fracture risk in osteoporotic postmenopausal women; moreover, BZA decreased the non-vertebral fracture risk in a subgroup of patients at high-risk for fracture in comparison to placebo. BZA showed no stimulating effects on endometrium and breast. BZA can be a valid option in management of osteopenia/osteoporosis in postmenopause.
An independent search of citations was conducted using the PubMed database for all literature as of February 2013. Phase II-III studies using the terms "tamoxifen," "toremifene," "raloxifene," "anastrozole," "letrozole," "exemestane," "fulvestrant," "leuprolide," "flutamide," "bicalutamide," "nilutamide," "fluoxymesterone," "estradiol," "octreotide," "megestrol," "medroxyprogesterone acetate," "enzalutamide," and "abiraterone" were searched.
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Tamoxifen elevates the risk of endometrial tumours in women and alpha-(N(2)-deoxyguanosinyl)-tamoxifen adducts are reportedly present in endometrial tissue of patients undergoing therapy. Given the widespread use of tamoxifen there is considerable interest in elucidating the mechanisms underlying treatment-associated cancer. Using a combined experimental and multivariate statistical approach we have examined the mutagenicity and potential consequences of adduct formation by reactive intermediates in target uterine cells. pSP189 plasmid containing the supF gene was incubated with alpha-acetoxytamoxifen or 4-hydroxytamoxifen quinone methide (4-OHtamQM) to generate dG-N(2)-tamoxifen and dG-N(2)-4-hydroxytamoxifen, respectively. Plasmids were replicated in Ishikawa cells then screened in Escherichia coli. Treatment with both alpha-acetoxytamoxifen and 4-OHtamQM caused a dose-related increase in adduct levels, resulting in a damage-dependent increase in mutation frequency for alpha-acetoxytamoxifen; 4-OHtamQM had no apparent effect. Only alpha-acetoxytamoxifen generated statistically different supF mutation spectra relative to the spontaneous pattern, with most mutations being GC-->TA transversions. Application of the LwPy53 algorithm to the alpha-acetoxytamoxifen spectrum predicted strong GC-->TA hotspots at codons 244 and 273. These signature alterations do not correlate with current reports of the mutations observed in endometrial carcinomas from treated women, suggesting that dG-N(2)-tam adduct formation in the p53 gene is not a prerequisite for endometrial cancer initiation in women.
In multicenter studies, one often needs to make inference about a population survival curve based on multiple, possibly heterogeneous survival data from individual centers. We investigate a flexible Bayesian method for estimating a population survival curve based on a semiparametric multiresolution hazard model that can incorporate covariates and account for center heterogeneity. The method yields a smooth estimate of the survival curve for "multiple resolutions" or time scales of interest. The Bayesian model used has the capability to accommodate general forms of censoring and a priori smoothness assumptions. We develop a model checking and diagnostic technique based on the posterior predictive distribution and use it to identify departures from the model assumptions. The hazard estimator is used to analyze data from 110 centers that participated in a multicenter randomized clinical trial to evaluate tamoxifen in the treatment of early stage breast cancer. Of particular interest are the estimates of center heterogeneity in the baseline hazard curves and in the treatment effects, after adjustment for a few key clinical covariates. Our analysis suggests that the treatment effect estimates are rather robust, even for a collection of small trial centers, despite variations in center characteristics.