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.

Effect of letrozole in carcinogen-plus-estrogen-induced endometrial hyperplasia in mice

PURPOSE: To evaluate the effects of letrozole (Ltz) in carcinogen+estrogen-induced endometrial hyperplasia. METHODS: BALB/c female mice were divided into four groups of 12 animals each receiving an intrauterine dose of N-ethyl-N-nitrosourea (ENU) and weekly subcutaneous injections of estradiol hexaidrobenzoate (EHB), except for group I(control). The groups were divided in I (control), II (ENU+EHB), III (ENU+EHB+MPA) and IV (ENU+EHB+Ltz). Group III also received intramuscular injections of MPA (medroxy progesterone acetate) every four weeks, while group IV received oral doses of Ltz daily. At the end of 16 weeks, the animals were sacrificed, and blood samples were collected for the measurement of serum estradiol and progesterone levels. Uterine histological sections were made to evaluate the presence of endometrial proliferative lesions. Differences between groups were evaluated with student's t test, ANOVA and chi-square test. RESULTS: Groups ENU+EHB, ENU+EHB+MPA and ENU+EHB+Ltz showed varying degrees of endometrial hyperplasia. The incidence of hyperplasia in groups ENU+EHB and ENU+EHB+Ltz was higher and more severe than in group ENU+EHB+MPA. Control group showed lower levels of serum estradiol than the other groups. CONCLUSION: There was no evidence that letrozole could act as an antiestrogenic drug in the development of endometrial proliferative lesions.

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.

Cáncer de próstata y apoptosis / Prostate Cancer and Apoptosis

El cáncer de próstata presenta una progresión andrógeno-dependiente mediada por el receptor de andrógeno (AR), por lo que el bloqueo androgénico es la terapia estándar para su tratamiento en estado avanzado. Sin embargo, a pesar de una sensibilidad inicial, estos cánceres usualmente evolucionan hacia un estado hormono-resistente. Esta resistencia puede ser debida a una amplificación del gen AR, a sus mutaciones y al aumento en la expresión de proteínas co-activadoras. Igualmente, el receptor AR puede permanecer activo, independientemente de la fijación del ligando por fosforilación de factores de crecimiento y de citosinas. Adicionalmente, hay otras posibles vías independientes del receptor AR, como lo ejemplifica la adquisición del fenotipo neuroendocrino. En esta revisión se examinan tanto los mecanismos moleculares involucrados en la progresión del cáncer de próstata así como la forma en que sus células evaden la apoptosis.

Prostate cancer presents an androgen-dependent growth mediated by the androgen receptor (AR). Androgen pathway blockage is the standard therapy for the treatment of prostate cancer at an advanced stage. In spite of an initial sensitivity, prostate cancer usually becomes refractory to hormone treatment. This resistance can be due to the amplification of the AR gene, AR mutations and the increase in co-activator protein expression. Likewise, growth factors and cytokines can induce AR phosphorylation, independently of ligand fixation. Moreover, there are other AR-independent pathways, such as the acquisition of the neuroendocrine phenotype. In this review, we examine the molecular mechanisms that are involved in the progression of prostate cancer, as well as the ways its cells evade apoptosis.

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.

Primary octreotide LAR therapy in GH-secreting pituitary adenoma.

A case of a 54-year-old male with active acromegaly and severe aortic stenosis treated primarily with octreotide LAR 20 mg/ IM/month for six months is reported here. His serum growth hormone level declined and was sustained throughout the period of six months (basal GH level 21.8 ng/ml; 1.2 ng/ml six months after therapy; mean+/-SD during six months of therapy 1.36+/-0.34 ng/ml; range 0.9 - 1.9 ng/ml). The post-treatment, postgadolinium, T1 weighted sagittal magnetic resonance images showed disappearance of the growth hormone secreting adenoma. The use of octreotide LAR as primary therapy in active acromegaly is discussed along with a brief review of literature.

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.

The Effects of Tamoxifen on Human Hepatocelluar Carcinoma Cell Proliferation and Transforming Growth Factor-beta1 Expression / 대한간학회지

BACKGROUND/AIMS: Tamoxifen has been tried in patients with hepatocellular carcinoma (HCC), however, its inhibitory mechanism remains unknown. In this study, we evaluated the effects of tamoxifen on HCC cell growth and the expression of transforming growth factor-beta1 (TGF-beta1) which had been known as an important cytokine in growth of HCC. METHODS: Hep 3B cells were cultivated in estrogen free media with 0.1 micro M, 0.5 micro M, 1 micro M, 5 micro M, and 10 micro M of tamoxifen for 6 days. Viable cells were counted daily and the TGF-beta1 concentrations in supernatant were measured by ELISA method. RESULTS: The number of viable HCC cells increased rather significantly after the treatment of tamoxifen of lower concentration (0.1 micro M) compared with that of the control (2.59x10(7) vs. 1.97x10(7); p<0.05). As the concentration of treated tamoxifen was higher, the number of viable HCC cells became gradually less, resulting in the significant decrease of it at the highest concentration (10 micro M) compared with that of the control (1.40x10(7) vs. 1.97x10(7); p<0.05). TGF-beta1 concentration in supernatant of tamoxifen-treated samples was significantly decreased compared with those of controls, regardless of the amount of treated tamoxifen. CONCLUSIONS: These results suggest that tamoxifen may suppress TGF-beta1 expression to an extent, although it has different effects on the proliferation of HCC cells, at the various concentrations of this agent in vitro. Such effects of tamoxifen on TGF-beta1 expression may inhibit the growth and progression of HCCs over-expressing TGF-beta1 in vivo.

In vitro resistance of leukaemic blasts to prednisolone in bcr-abl positive childhood acute lymphoblastic leukaemia.

BACKGROUND & OBJECTIVES: Although the outcome of children with acute lymphoblastic leukaemia (ALL) has improved dramatically over the last decade, some children still fare poorly and relapses are seen. The sensitivity of leukaemic cells to corticosteroids has emerged as an important prognostic factor in ALL. The t(9,22) translocation, resulting in the bcr-abl fusion gene, is a non-random translocation found in B-lineage acute lymphoblastic leukaemia. It is also known to be an independent poor prognostic factor for long-term disease free survival. We studied the association between the presence of bcr-abl fusion gene and in vitro prednisolone resistance in children with B-lineage acute lymphoblastic leukaemia at diagnosis. METHODS: A total of 23 children (aged 1-16 yr, median age: 12 yr) with B-lineage acute lymphoblastic leukaemia at diagnosis were included in the study. The presence of bcr-abl fusion gene was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and the in-vitro resistance to prednisolone was measured by short term colorimetric methyl thiazol tetrazolium (MTT) assay. RESULTS: A median LD50 (lethal dose for 50% cells) for prednisolone in bcr-abl positive children (n=7) was 1.6 mg/ml (range: 0.25-5.0 mg/ml) and that of bcr-abl negative children (n=16) was 0.35 mg/ml (range 0.62-1.0 mg/ml). The median LD50 for prednisolone differed significantly between the bcr-abl positive and negative groups of children with acute lymphoblastic leukaemia (P<0.005). INTERPRETATION & CONCLUSION: This is probably the first report to show that leukaemic blasts of bcr-abl positive children with ALL are about four-fold resistant to prednisolone as compared to blasts from bcr-abl negative children. This suggests that one of the reasons for the poor prognosis of bcr-abl positive ALL could be a lower steroid sensitivity.

Drug sensitivity assay for leukaemic cells by flow cytometry.

BACKGROUND & OBJECTIVES: Drug sensitivity assays are useful in oncology practice for evaluating the sensitivity of malignant cells to anti-cancer drugs. The usefulness of such assays for the prediction of clinical response to therapy has also been demonstrated. The existing methods used for this purpose are time consuming and labour intensive. Here we report a simplified flow cytometry based assay for evaluating the in vitro drug sensitivity of leukaemic cells. METHODS: The chemo-sensitivity of three human leukaemic cell lines (a lymphoblastoid cell line, Jurkat; an erythroleukaemic cell line, K 562 and a myelomonocytic cell line HL-60) was investigated by flow cytometry. Flow cytometry was used to determine LD50 (50% inhibitory concentration) for prednisolone on Jurkat and daunorubicin on HL 60 and K 562 cell lines respectively. Per cent cell death could directly be assessed on a flow cytometer by measuring the fluorescence after staining with propidium iodide (PI). For comparison MTT assay was also performed using prednisolone on Jurkat and daunorubicin on HL-60. RESULTS: Cytotoxic effect of drugs was found to be dose dependent. Mean LD50 of prednisolone for Jurkat cells by flow cytometry was 0.805 +/- 0.058 mg/ml and by MTT assay 0.866 +/- 0.115 mg/ml. Mean LD50 of daunorubicin for HL-60 was 1.96 +/- 0.05 micrograms/ml by flow cytometry and 1.90 +/- 0.282 micrograms/ml by MTT assay. The mean LD50 of daunorubicin to K 562 was 0.49 +/- 0.049 mg/ml by the flow cytometry method. The inter-assay variation for the LD50 by flow cytometry based assay was found to be 6, 14 and 10 per cent for Jurkat, HL-60 and K 562 respectively. INTERPRETATION & CONCLUSION: We report a flow cytometry based drug-sensitivity assay for leukaemic cells, which uses a single dye staining and is rapid, technically simple and reproducible. The results compare well with the more commonly used MTT assay, which is labour intensive and time consuming. The limitation of our method is that it can only be used for studying cells in suspension and is therefore not suitable for adherent cell lines.

Avaliação da resposta terapêutica aos análogos da somatostatina em uma linhagem de tumores hipofisários somato-mamotróficos transplantáveis do rato / Evaluation of the therapeutical reply to the analogous ones of the somatostatina in an ancestry of pituitary somato-mamotrophic transplantable tumor of the rat

Foram avaliados os efeitos de um análogo da somotostatina, a octreotida, sobre a secreção hormonal e a proliferação celular de tumores hipofisários do rato, secretores de PRL (SMtTW2) ou GH e PRL (SMtTW10), considerados como modelos experimentais de adenomas mano-somatotróficos...

Role of bio-metal Fe(III) in anticancer behaviour of tamoxifen.

Physicochemical, microbial and pharmacological studies on Fe (III)--Tamoxifen complex have been carried out in solid and aqueous phases. On the basis of elemental analysis, polarographic studies, amperometric titrations and IR spectral studies the probable formula for the complex has been worked out to be 1:1, Fe(III)--Tamoxifen. A tentative structure has been suggested to the complex. The metal ligand interaction has been studied using polarographic method at 27 degrees +/- 1 degree C and at ionic strength of mu = 1.0 (KCl). Microbial studies on the complex was carried out against various pathogenic bacteria and fungi using Raper's method. Mouse sarcoma cell line 180 and Balb/C mice were used for the anticancer screening of solid complex, in vitro and in vivo, respectively. The results of microbial and pharmacological studies with the M:Drug complex revealed that the complex is more potent as compared to the pure drug as regards to its anticancer activity. As such Fe (III) Tamoxifen complex may be recommended to the therapeutic experts for its possible use as more potent anticancer drug.