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

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

Elección del mejor antidepresivo en pacientes con cáncer de mama en tratamiento con tamoxifeno: revisión de la evidencia básica y clínica / Antidepressants agents in breast cancer patients using tamoxifen: review of basic and clinical evidence

Tamoxifen (Tmf), is a standard of care for women with estrogen receptor positive (ER+) breast cancer. Endoxifen is a Tmf metabolite generated by cytochrome P450 2D6 (CYP2D6). Antidepressive agents (AD) are often prescribed to women with breast cancer not only for depression, but also for anxiety and hot flashes. Some AD are substrates or inhibitors of the Tmf metabolic pathway. Therefore there may be interactions when Tmf and AD are prescribed simultaneously. Oncologic protection afforded by Tmf may become less effective or null when AD are indicated, especially in poor metabolizing patients. We performed an update of the literature about the criteria for choosing AD in women receiving Tmf. Tricyclic AD, paroxetine and fluoxetine should be avoided in patients receiving Tmf, because they are strong inhibitors of CYP2D6. Bupropion, duloxetine and sertraline are only moderate inhibitors of the cytochrome and are not contraindicated. Citalopram, desvenlafaxine, escitalopram, milnacipran and venlafaxine are recommended, because they do not influence the metabolism and clinical efficacy of Tmf and have fewer drug interactions. However, other additional pharmacological and clinical issues should be considered when choosing an antidepressant in women with breast cancer.

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

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.

Tamoxifen Induces Apoptosis of Leishmania major Promastigotes in Vitro

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.

Boys in white: um clássico da pesquisa qualitativa completa cinquenta anos / Boys in white: a classic of qualitative research turns 50

O artigo analisa o livro Boys in white: student culture in medical school, de Howard S. Becker, Blanche Geer, Everett C. Hughes e Anselm Strauss, considerado um dos modelos de pesquisa qualitativa em sociologia. A análise aborda as trajetórias dos autores, do livro, da pesquisa qualitativa e dos estudantes de medicina, enfatizando sua importância nas origens da sociologia médica e da sociologia da educação médica. Na trajetória dos autores são apresentados aspectos biobibliográficos; na da pesquisa qualitativa, o modo como essa metodologia de investigação atravessa a construção do trabalho de campo; e na dos estudantes, sua forma de atravessar os primeiros anos da escola médica e construir sua própria “cultura do estudante”.

This article analyzes Boys in white: student culture in medical schoolby Howard S. Becker, Blanche Geer, Everett C. Hughes and Anselm Strauss, considered a model of qualitative research in sociology. The analysis investigates the trajectories of the authors, the book, qualitative analysis, and the medical students, emphasizing their importance in the origins of medical sociology and the sociology of medical education. In the trajectory of the authors, bibliographical information is given. The trajectory of qualitative research focuses on how this methodology influences the construction of the field. The investigation of the students’ trajectory shows how they progress through their first years at medical school to build their own student culture.

Differential toxicological endpoints of di(2-ethylhexyl) phthalate (DEHP) exposure in MCF-7 and MDA-MB-231 cell lines: Possible estrogen receptor α (ERα) independent modulations.

Wide spread use of Di-(2-ethylhexyl) phthalate (DEHP) has made it a ubiquitous contaminant in today’s environment, responsible for possible carcinogenic and endocrine disrupting effects. In the present investigation an integrative toxico-proteomic approach was made to study the estrogenic potential of DEHP. In vitro experiments carried out with DEHP (0.1-100 μM) induced proliferations (E-screen assay) in human estrogen receptors-α (ERα) positive MCF-7 and ERα negative MDA-MB-231 breast cancer cells irrespective of their ERα status. Further, DEHP suppressed tamoxifen (a potent anti-breast cancer drug) induced apoptosis in both cell types as shown by flowcytometric cell cycle analysis. Label-free quantitative proteomics analysis of the cell secretome of both the cell lines indicated a wide array of stress related, structural and receptor binding proteins that were affected due to DEHP exposure. The secretome of DEHP treated MCF-7 cells revealed the down regulation of lactotransferrin, an ERα responsive iron transport protein. The results indicated that toxicological effects of DEHP did not follow an ERα signaling pathway. However, the differential effects in MCF-7 and MDA-MB-231 cell lines indicate that ERα might have an indirect modulating effect on DEHP induced toxicity.

Stereological Comparison of the Effects of Pentoxifylline, Captopril, Simvastatin, and Tamoxifen on Kidney and Bladder Structure After Partial Urethral Obstruction in Rats

PURPOSE: Limited studies have shown antifibrotic effects of pentoxifylline, captopril, simvastatin, and tamoxifen. No comparisons are available of the effects of these drugs on prevention of renal and bladder changes in partial urethral obstruction (PUO). MATERIALS AND METHODS: The rats were divided into six groups (n=7). The sham-operated rats (group I) only underwent laparotomy and did not receive any treatments. The PUO groups (group II-VI) received normal saline (PUO+NS), pentoxifylline (100 mg/kg/d; PUO+PEN), captopril (35 mg/kg/d; PUO+CAP), simvastatin (15 mg/kg/d; PUO+SIM), or tamoxifen (10 mg/kg/d; PUO+TAM) by gavage for 28 days. Then, the volume and/or length of the kidney components (tubules, vessels, and fibrous tissue) and the bladder components (epithelial and muscular layers, fibrous tissue, fibroblast and fibrocyte number) were quantitatively evaluated on the microscopic sections by use of stereological techniques. RESULTS: The volume of renal and bladder fibrosis was significantly ameliorated in the PUO+PEN group, followed by the PUO+CAP, PUO+SIM, and PUO+TAM groups. Also, the volume and length of the renal tubules and vessels and bladder layers were more significantly protected in the PUO+PEN group, followed by the PUO+CAP, PUO+SIM, and PUO+TAM groups. CONCLUSIONS: Treatment of PUO with PEN was more effective in the prevention of renal and bladder fibrosis and in the preservation of renal and bladder structures.

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

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

Influence of estradiol and triiodothyronine on breast cancer cell lines proliferation and expression of estrogen and thyroid hormone receptors / Efeito do estradiol e da triiodotironina na proliferação de linhagens celulares de câncer de mama e na expressão de receptores de estrógeno e hormônio tireoidiano

OBJECTIVE: To better understand the estrogen (E2) agonist action of triiodothyronine (T3) the effects of these hormones on ER negative MDA-MB-231 breast cancer cells were compared with those on S30, a clone of MDA-MB-231 stably transfected with ERα cDNA, in terms of proliferation and modulation of hormone receptors. RESULTS: Growth experiments showed that MDA-MB-231 was not modulated by any hormone or tamoxifen (TAM). Treatment with E2, 10-8M or 10-9M had little effect on S30 proliferation. T3 at 10-8M significantly inhibited proliferation. This effect was not reverted by TAM. Treatments with 10-8M concentration of E2 or T3 reduced ERα gene expression in S30, an effect partially blocked by association with TAM, with no effect on TR expression. These results suggest that, in S30, 10-8M T3 has a similar action to E2 relative to ERα gene modulation. CONCLUSIONS: Such results emphasize the need of determining T3 levels, before the introduction of antiestrogenic forms of treatment in breast cancer patients.

OBJETIVO: Para compreender melhor a ação da triiodotironina (T3) agonista de estrógeno (E2), foram comparados os efeitos destes hormônios em células de câncer de mama MDA-MB-231 ER negativas com um clone de MDA-MB-231, transfectado estavelmente com o cDNA de ERα (S30), em termos de proliferação e modulação dos receptores hormonais. RESULTADOS: Experimentos de crescimento mostraram que MDA-MB-231 não foi modulada por qualquer hormônio ou pelo tamoxifeno (TAM). O crescimento de S30 foi essencialmente inalterado por tratamento com E2 10-9M ou 10-8M, mas T3 10-8M inibiu significativamente a proliferação quando comparada a ambas concentrações de E2. Esse efeito não foi revertido pelo TAM, sugerindo um resultado não genômico, independente de ERE. Tratamentos com 10-8M de E2 ou de T3 reduziram a expressão do gene ERα em S30, efeito parcialmente impedido pela associação com TAM, sem efeito na expressão de TR. Os resultados sugerem que, em S30, T3 10-8M tem ação semelhante ao E2 com relação à modulação do gene ERα. CONCLUSÕES: Esses resultados enfatizam a necessidade de dosagem de T3 circulante antes da introdução do tratamento antiestrogênico no câncer de mama.

Efeitos do tamoxifeno sobre a expressão das proteínas TGF-β e p27 em pólipos e endométrio adjacente de mulheres após a menopausa / Effects of tamoxifen on the expression of TGF-β and p27 proteins in polyps and adjacent endometrium in postmenopausal women

OBJETIVO:avaliar os efeitos do uso do tamoxifeno sobre a expressão das proteínas TGF-β e p27 em pólipos e endométrio adjacente de mulheres após a menopausa. MÉTODOS: estudo prospectivo, com 30 mulheres, após a menopausa com diagnóstico de câncer de mama, usuárias de tamoxifeno (20 mg/dia), que apresentavam diagnóstico de pólipo endometrial suspeito por meio de ultrassonografia transvaginal, submetidas à histeroscopia diagnóstica e cirúrgica para retirada dos pólipos e do endométrio adjacente. Realizado estudo imunoistoquímico para verificar a expressão das proteínas TGF-β e p27 nos pólipos e no endométrio adjacente. A quantificação dessas proteínas foi realizada por morfometria. RESULTADOS: a média de idade foi 61,7 anos; média da idade na menopausa, 49,5 anos; e o tempo médio de uso do tamoxifeno, de 25,3 meses. A concentração média de células positivas para proteína TGF-β no pólipo epitélio glandular e estroma foi 62,6±4,5 células/mm². Para a p27, no pólipo epitélio glandular, foi de 24,2±18,6 cel/mm² e estroma 19,2±15,2 cel/mm². Não houve diferença significante entre a expressão do TGF-β e p27 nos epitélios glandulares dos pólipos e do endométrio adjacente. A expressão das proteínas do pólipo e endométrio adjacente com os seus respectivos epitélios glandular e estromal apresentou diferença significativa para a proteína p27 (r=0,9, p<0,05). CONCLUSÕES: concluímos que a expressão do TGF-β não está relacionada ao efeito do tamoxifeno sobre o crescimento dos pólipos endometriais, mas a ausência de malignização dos pólipos induzida pelo tamoxifeno pode ser explicada pela alta expressão da proteína p27 no seu epitélio glandular.

PURPOSE: to evaluate the effects of tamoxifen on the expression of TGF-β and p27 proteins in polyps and adjacent endometrium of women after menopause. METHODS: prospective study with 30 post-menopausal women with diagnosis of breast cancer, taking tamoxifen (20 mg/day), presenting diagnosis of suspect endometrial polyps through transvaginal ultrasonography, and submitted to diagnostic and surgical hysterectomy to withdraw the polyps and adjacent endometrium. A immunohistochemical study has been done to verify the expression of the TGF-β and p27 proteins in the polyps and adjacent endometrium. These proteins' quantification has been done by morphometry. RESULTS: the patients' average age was 61.7 years old; their average age at the menopause onset was 49.5; and the average of using tamoxifen was 25.3 months. The average concentration of positive cells for TGF-β protein in the glandular and stroma polyp epithelium was 62.6±4.5 cells/mm². For the p27, in the glandular polyp epithelium, it was 24.2±18.6 cells/mm² and for the stroma, 19.2±15.2 cells/mm². There was no significant difference between the expression of TGF-β and p27 in the glandular epithelial form the polyps and the adjacent endometrium. The expression of proteins in the polyp and adjacent endometrium with its respective glandular and stroma epithelium showed a significant difference for the p27 protein (r=0.9, p<0.05). CONCLUSIONS: we have concluded that the TGF-β expression is not related to the effect of tamoxifen on the growing of endometrial polyps, but the absence of polyps' malignization by tamoxifen may be explained by the high expression of p27 protein in its glandular epithelium.

Un síntoma cuasi parapsicológico: palinopsia

La parapsicología se refiere al estudio de ciertos tipos de fenómenos paranormales. Paranormal conciernea una experiencia que no parece ser explicable en términos del conocimiento científico o de nuestra comprensión de hechos cotidianos. La realidad científica del fenómeno parapsicológico y la validez científica de sus investigaciones, a menudo son áreas de frecuente disputa y crítica. Hasta ahora la psicología formal la caracteriza como una pseudociencia. La palinopsia es un raro síntoma caracterizado por el fenómeno ilusorio de perseveración y/o recurrencia de imágenes visuales luego de haber sido removido el estímulo excitatorio. Es una distorsión del procesamiento de imágenes en el sistema visual causado por lesiones unilaterales o bilaterales de variado origen que afectan las áreas posteriores de los hemisferios cerebrales, toxicidad o efectos colaterales de drogas terapéuticas, una extensa lista de condiciones misceláneas y aún en sujetos normales. A despecho de su rareza, existe abundante literatura al respecto posiblemente por su carácter intrigante o por su naturaleza pseudo-parapsicológica. Los autores presentan los casos de 6 pacientes, dos de los cuales estaban recibiendo tamoxifeno, una droga hasta el presente no reconocida como causa de este fenómeno

Parapsychology is the scientific study of certain types of paranormal phenomena. The “paranormal” (beside or beyond the normal) refers to unusual experiences that do not seem to be explainable in terms of our everyday understanding or known scientific principles. The scientificreality of parapsychological phenomena and the validity of scientific parapsychological research is amatter of frequent dispute and criticism. The field is regarded by some critics as a pseudoscience. Palinopsia is a rare symptom characterized by the illusory phenomenon of perseverance or recurrence of visual images after removal of the exciting stimulus. It is a distortion of the processing in the visual system caused by unilateral o bilateral lesions of various kinds, such as toxicity or side effects of drugs, as well as an array of miscellaneous conditions, that affect posterior areas of the cerebral hemispheres in normal subjects. Despite its rarity, there is abundance of literature on the subject, possibly because of the intriguing, quasiparapsychologic nature of the symptom. Six patients were identified with the diagnosis of palinopsia o poliopsia of whom two were taking the drug tamoxifen not previously described in the literature

Estrogen receptor independent neurotoxic mechanism of bisphenol A, an environmental estrogen

Bisphenol A (BPA), a ubiquitous environmental contaminant, has been shown to cause developmental toxicity and carcinogenic effects. BPA may have physiological activity through estrogen receptor (ER) -alpha and -beta, which are expressed in the central nervous system. We previously found that exposure of BPA to immature mice resulted in behavioral alternation, suggesting that overexposure of BPA could be neurotoxic. In this study, we further investigated the molecular neurotoxic mechanisms of BPA. BPA increased vulnerability (decrease of cell viability and differentiation, and increase of apoptotic cell death) of undifferentiated PC12 cells and cortical neuronal cells isolated from gestation 18 day rat embryos in a concentration-dependent manner (more than 50 micrometer). The ER antagonists, ICI 182,780, and tamoxifen, did not block these effects. The cell vulnerability against BPA was not significantly different in the PC12 cells overexpressing ER-alpha and ER-beta compared with PC12 cells expressing vector alone. In addition, there was no difference observed between BPA and 17-beta estradiol, a well-known agonist of ER receptor in the induction of neurotoxic responses. Further study of the mechanism showed that BPA significantly activated extracellular signal-regulated kinase (ERK) but inhibited anti-apoptotic nuclear factor kappa B (NF-kappaB) activation. In addition, ERK-specific inhibitor, PD 98,059, reversed BPA-induced cell death and restored NF-kappaB activity. This study demonstrated that exposure to BPA can cause neuronal cell death which may eventually be related with behavioral alternation in vivo. However, this neurotoxic effect may not be directly mediated through an ER receptor, as an ERK/NF-kappaB pathway may be more closely involved in BPA-induced neuronal toxicity.

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

OBJETIVO: Avaliar a ação dos estrogênios conjugados eqüinos e do tamoxifeno na histomorfologia da tireóide de ratas. MÉTODO: Estrogênios conjugados eqüinos são ministrados clinicamente como terapia estrogênica e contêm formulação complexa com muitos tipos de estrogênios que diminuem os sintomas da pós-menopausa. Trinta ratas adultas ooforectomizadas foram divididas aleatoriamente em três grupos: GI – veículo (propilenoglicol); GII - ECE 200 µg/Kg por dia; e GIII – TAM 1 mg/Kg por dia. Acrescentou-se ainda um grupo de 10 animais com os ovários intactos e tratados com veículo (GIV). Todos os animais foram tratados por gavagem durante 50 dias consecutivos, ao final foram coletadas amostras do sangue e a tireóide removida e processada para análise morfológica e imunohistoquímico para avaliar o PCNA. RESULTADOS: A maior altura das células foliculares foi observada nos animais tratados com ECE (14,90 ± 0,20 µm), TAM (14,90 ± 0,10 µm) e no grupo com ovários intactos (15,10 ± 0,50 µm), comparando-se aos controles ovariectomizados (GI) (9,90 ± 0,20 µm) (p<0,001). A maior área folicular foi detectada nos grupos tratados com ECE (2.225 ± 51 µm2) e com TAM (2.127 ± 67 µm2), comparado ao veículo (5.016 ± 53 µm2) em animais ooforectomizados. Os níveis de T4 e T3 nos grupos tratados com ECE, com TAM e no grupo com ovários intactos foram maiores do que no grupo tratado com veículo (p<0,001). O índice do PCNA no grupo tratado com veículo foi menor do que em todos os outros grupos. CONCLUSÃO: Nossos dados sugerem que a administração de ECE e TAM resulta em atividade proliferativa na tireóide.

Selective estrogen receptor modulators (SERMS) / Moduladores seletivos do receptor estrogênico (SERMs)

Hormone receptors and, specifically, estrogen receptors were described about four decades ago. For estrogens, there are two receptors, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta). The two receptors are coded by different genes and their tissue expression varies across organs. ERalpha is predominantly expressed in reproductive tissues (uterus, breast, ovaries) liver and central nervous system, whereas ERbeta is expressed in other tissues such as bone, endothelium, lungs, urogenital tract, ovaries, central nervous system and prostate. More than seventy molecules that belong to the SERMS class have been described. There are 5 chemical groups: triphenylethylenes, benzotiophenes, tetrahydronaphtylenes, indoles and benzopyrans. All of these non-hormonal compounds are capable of activating the ER, reduce bone turnover rate and, as an antiresorptive, clearly improve bone density. Estrogens reduce bone turnover rate and, as an antiresorptive, clearly improve bone density. They are also beneficial for the relief of menopausal symptoms. An ongoing debate that extends over the decades, relates to to overall benefit/risk profile of estrogen or estrogen-progestin therapy since these therapies can increase the risk of serious health disorders, such as breast cancer. SERMs have increased our understanding of hormone-receptor regulatory mechanisms. Their development has permitted a targeted efficacy profile avoiding some of the side effects of the hormone therapy. Their clinical utility relies today mostly on the effects on breast cancer and bone.

Os receptores hormonais e especificamente os receptores estrogênicos, foram descritos há cerca de 40 anos. Para os estrógenos, existem dois tipos: o alfa (ERalfa) e os beta (ERbeta), os quais são codificados por diferentes genes e sua expressão tissular varia de tecido para tecido. O ERalfa se expressa predominantemente no aparelho reprodutivo (útero, mamas, ovários), fígado e sistema nervoso central (SNC). O ERbeta se expressa em outros tecidos como osso, endotélio, pulmões, urogenital, além dos ovários, SNC e próstata. Mais de setenta moléculas pertencentes ao grupo dos SERMs têm sido descritas, em 5 grupos químicos: trifeniletilenos, benzotiofenos, tetrahidronaftilenos, indols e benzopiranos. Todos estes compostos não hormonais são capazes de ativar o ER, reduzindo a remodelação óssea e melhorando a densidade mineral óssea. Os estrógenos reduzem a remodelação óssea e aumentam a densidade mineral óssea, como também melhoram os sintomas da menopausa. Um debate permanente existe a respeito da relação risco/benefício da terapia estrógeno-progestínica, em virtude do aumento do risco de problemas de saúde mais sérios como câncer de mama. Os SERMs aprimoraram o conhecimento sobre os mecanismos de regulação hormônio-receptor, e o seu desenvolvimento permitiu uma eficiente modalidade de ação terapêutica hormonal, evitando-se alguns dos efeitois adversos da terapia hormonal per si.

Estrogenic action of tamoxifen in women treated with leutinizing hormone releasing-hormone agonist goserelin [zoladex]: lack of shrinkage of uterine fibroids

Six premenopausal women with uterine fibroids were treated with a combination of tamoxifen 20mg/d and Zoladex 3.6mg every 28 days for a total of 24 weeks. Results were compared with those from six women matched for pretreatmented uterine volume who had been treated with zoladex alone. During combined therapy, plasma and urinary estrogen concentrations were significantly lower than during Zoladex alone, whereas sex hormone binding globulin concentrations were significantly higher. Plasma LH and FSH concentration were both suppressed in contrast with results during Zoladex alone when FSH levels remained with the pretreatment range. None of the women on combined therapy bled in response to the endocrine change of the internal treatment cycle. Despite this profound pituitary-ovarian suppression. There was no significant change in uterine volume during combined therapy. The results suggest that tamoxifen is acting as an estrogen agonist in women rendered hypoestrogenic with luteinizing releasing hormone agonist. We failed to demonstrate any decrease in size of uterine fibroids when the antiestrogen tamoxifen was administered continuosly as a single agent. However, this lack of response was attributable to significant elevation of estrogen concentration during tamoxifen therapy

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

OBJETIVO: Considerando-se que importantes avanços científicos têm sido obtidos através de estudos com Diabetes mellitus experimental, e que a ação do tamoxifeno em humanos permanece obscura, o presente trabalho objetiva acompanhar as modificações promovidas pelo diabetes e tamoxifeno no perfil eletroforético das proteínas plasmáticas. MÉTODOS: Foram utilizados 27 ratos fêmeas Wistar (180-220g peso corporal), divididos randomicamente em 5 grupos: C1 (n=3, receberam veículo), C2 (n=3, sem tratamento), T (n=5, tratados com tamoxifeno, 0,3mg/kg/dia), D (n=8, diabéticos experimentais por estreptozotocina, 45mg/Kg) e DT (n=8, diabéticos tratados com tamoxifeno). A eletroforese foi realizada em acetato de celulose, pH 8,6-8,8, cuba TECNOW, e as fitas foram coradas em Ponceau S. As proteínas totais foram determinadas pelo método do Biureto (Kit Labtest). Os proteinogramas foram obtidos em densitômetro BioSystems BTS-235. RESULTADOS: Albumina diminuiu progressivamente nos grupos T, D e DT; a fração a1 aumentou nos grupos T e DT; a fração a2 aumentou nos grupos T e D, havendo efeito aditivo no grupo DT; a fração b aumentou nos grupos T e D; a fração g aumentou nos grupos T, D e DT. CONCLUSÃO: Os resultados indicam uma resposta de fase aguda, com efeito aditivo do tamoxifeno e diabetes, sugerindo uma provável lesão hepática.

Effects of Tamoxifen on the Voltage-dependent Ionic Currents in Mouse Colonic Smooth Muscle Cells / 대한소화기학회지

BACKGROUND/AIMS: Tamoxifen is a widely used anticancer drug for breast cancer with frequent gastrointestinal side effects. Changes in gastrointestinal motility is associated with altered activities of membrane ion channels. Ion channels have important role in regulating membrane potential and cell excitability. This study was performed to investigate the effects of tamoxifen on the membrane ionic currents in colonic smooth muscle cells. METHODS: Murine colonic smooth muscle cells were isolated from the proximal colon using collagenase, and the membrane currents were recorded using a whole-cell patch clamp technique. RESULTS: Two types of voltage-dependent K+ currents were recorded (A-type and delayed rectifier K+ currents). Tamoxifen inhibited both types of voltage-dependent K+ currents in a dose-dependent manner. However, tamoxifen did not change the half-inactivation potential and the recovery time of voltage-dependent K+ currents. Chelerythrine, a protein kinase C inhibitor or phorbol 12, 13-dibutyrate, a protein kinase C activator did not affect the voltage-dependent K+ currents. Guanosine 5'-O-(2-thio-diphosphate) did not affect the tamoxifen-induced inhibition of voltage-dependent K+ currents. Tamoxifen inhibited voltage-dependent Ca2+ currents completely in whole-test ranges. CONCLUSIONS: These results suggest that tamoxifen can alter various membrane ionic currents in smooth muscle cells and cause some adverse effects on the gastrointestinal motility.

Cross-contamination with tamoxifen induces transgene expression in non-exposed inducible transgenic mice

Inducible transgenic mouse models that impose a constraint on both temporal and spatial expression of a given transgene are invaluable. These animals facilitate experiments that can address the role of a specific cell or group of cells within an animal or in a particular window of time. A common approach to achieve inducibility involves the site-specific recombinase ‘Cre’, which is linked to a modified version of one of various steroid hormone-binding domains. Thus, the expression of Cre is regulated such that a functional nuclear transgene product can only be generated with the addition of an exogenous ligand. However, critical requirements of this system are that the nuclear localization of the transgene product be tightly regulated, that the dosage of the inducing agent remains consistent among experimental animals and that the transgene cassette cannot express in the absence of the inducing agent. We used the Cre ER(T2) cassette, which is regulated by the addition of the estrogen antagonist tamoxifen to determine whether cross-contamination of tamoxifen between animals housed together can be a significant source of spurious results. We found that cross-contamination of exogenous tamoxifen does occur. It occurred in all animals tested. We suggest that the mechanism of contamination is through exposure to tamoxifen in the general environment and/or to coprophagous behavior. These results have important implications for the interpretation and design of experiments that use ‘inducible’ transgenic animals.

Estrogen receptor profiles: changes in mouse and rat mammary tumors by treatment with selective estrogen receptor modifiers

The aim of this work was to analyze the effect of estradiol [E2], medroxyprogesterone and the two selective estrogen receptor modulators [SERMs] [tamoxifen [Tam] and raloxifene [Ral]] on the estrogen receptor [ER] conformers profile performed by size exclusion HPLC in relation to hormone dependence of mammary tumors. Materials and Two types of mammary tumors were studied: tumors transplanted in BALB/c mice that are medroxyprogesterone acetate [MPA]-dependent for growth, and tumors induced in Sprague-Dawley rats by intraperitoneal injection of N-nitroso-N-methylurea [NMU]. Tumors from mice treated with MPA, E2, Tam or Ral and NMU-treated rats were analyzed and compared to that of control. The tumor conformer profiles were as follows: control and MPA-treated mice showed only one peak [oligomeric form]; E2-treated mice also showed only one peak [dimer]; Tam-treated mice showed one peak corresponding to a possible proteolytic fragment, and Ral-treated mice showed two peaks [oligomeric and a possible proteolytic fragment]. On the other hand, NMU-induced mammary tumors from rats showed three peaks [oligomeric, monomeric and proteolytic]. Our findings may indicate that SERMs affect the aggregation state of ER and thereby its ability to modulate genomic transcription mechanisms related to growth rate

Effects of estradiol and tamoxifen on proliferation of human breast cancer cells and human endometrial cells / 华中科技大学学报（医学）（英德文版）

The effects of estradiol and tamoxifen on the proliferation of estrogen receptor positive cells and the relationship between the tamoxifen tolerance and cell origin were investigated. The tissues of human endometrium and breast cancer were randomly selected following dissection for primary cell culture. After the breast cancer cells and endometrial cells were treated with 1 x 10(-8) mol/L estradiol and/or 1 x 10(-6) tamoxifen, 3H-labelled thymine nucleotide was used to trace the kinetics of cell proliferation. There was no significant difference in the inhibition on the human endometrial cells between tamoxifen-treated group (6.3%) and control group (6.4%), but tamoxifen could significantly inhibit the proliferation of the human breast cancer cells (45.84%) as compared with control group (52.72%). Moreover, tamoxifen could significantly stimulate the proliferation of tamoxifen resistant breast cancer cells (9.64%) as compared with control group (6.32%). Estradiol could significantly stimulate the proliferation of all the three kinds of cells as compare with control group. The combined use of estradiol and tamoxifen could inhibit the proliferation of the endometrial cells and breast cancer cells as compared with estradiol used alone, but on the tamoxifen resistant breast cancer cells, they could more significantly stimulate the proliferation than E2. It was concluded that E2 could stimulate the proliferation of these three kinds of cells. However, the inhibitive effects of tamoxifen on the proliferation of these cells were dependent on the estradiol.