A leishmaniose é uma doença parasitária de ampla distribuição, para a qual se dispõe de um limitado arsenal terapêutico. Trabalhos recentes mostraram que tamoxifeno é eficaz no tratamento de leishmaniose experimental. Nesse trabalho, avaliamos a terapia combinada de tamoxifeno com os fármacos utilizados atualmente no tratamento desta enfermidade. A interação entre os fármacos mostrou-se aditiva, tanto in vitro como in vivo. Em paralelo, analisamos os efeitos de tamoxifeno na biossíntese de esfingolipídios em Leishmania, sendo identificada a redução da síntese de fosfatidilinositol e inositolfosforil ceramida (IPC) e acúmulo de ceramida acilada. A redução na biossíntese de IPC não pode ser atribuída a redução no transporte de inositol, mas provavelmente está relacionada à inibição da enzima IPC sintase. Estes resultados indicam novas estratégias para superar as deficiências encontradas no tratamento de leishmaniose utilizando tamoxifeno, um fármaco clinicamente bem conhecido que exerce ações em múltiplos alvos em Leishmania. / Leishmaniasis is a parasitic disease with wide distribution and limited treatment. Recent reports demonstrate that tamoxifen is an effective drug for experimental leishmaniasis treatment. In this work, we evaluated the combined therapy of tamoxifen with current drugs used in leishmaniasis chemotherapy. The drug interaction was additive both, in vitro and in vivo. We also evaluated tamoxifen effect on in Leishmania sphingolipids biosynthesis. We found a reduction in phosphatidylinositol and inositol phosphorylceramide (IPC) synthesis and an accumulation of acilceramide. The reduction in IPC biosynthesis could not be assigned to the reduction observed in inositol transport, but probably is related to IPC synthase inhibition. These results show new strategies to circumvent shortcomings of leishmaniasis treatment using tamoxifen, a multitarget drug in Leishmania and widely used in the chemotherapy of breast cancer.

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Thesis (Ph. D.)--University of Virginia, 2008. / Includes bibliographical references. Also available online through Digital Dissertations.

Στις μετεμμηνοπαυσιακές γυναίκες με καρκίνο μαστού, θετικό για οιστρογονικούς υποδοχείς, μετά από χειρουργική θεραπεία, η μακροχρόνια χορήγηση της ταμοξιφαίνης (SERM πρώτης γενεάς), έχει αποδειχθεί ευεργετική. Ο σκοπός της παρούσης μελέτης, ήταν να διαπιστώσει, εάν οι πολυμορφισμοί του γονιδίου των ER (PvuII & XbaI του ERα και οι RsaI & AluI του Erβ), οι οποίοι έχουν συσχετισθεί με καρκίνο μαστού, σχετίζονται με το στάδιο του καρκίνου του μαστού ή την ανταπόκριση του ενδομητρίου στην μακροχρόνια αγωγή με ταμοξιφαίνη, στις μετεμμηνοπαυσιακές γυναίκες με καρκίνο του μαστού. Η μελέτη περιέλαβε 87 μετεμμηνοπαυσιακές γυναίκες με καρκίνο μαστού θετικό για οιστρογονικούς υποδοχείς, στις οποίες χορηγήθηκε ταμοξιφαίνη. Η μέση ηλικία των ασθενών ήταν 58,7± 4,7 έτη, και η μέση διάρκεια της αγωγής με ταμοξιφαίνη ήταν 3,9 ± 1,1 έτη. Το γονιδιακό DNA απομονώθηκε από τα λευκά αιμοσφαίρια δειγμάτων περιφερικού αίματος με την κλασσική μέθοδο φαινόλης - χλωροφορμίου. Τα κλάσματα των γονιδίων των ERα και Erβ, τα οποία συμπεριελάμβαναν τις θέσεις των πολυμορφισμών, πολλαπλασιάσθηκαν με την αλυσιδωτή αντίδραση πολυμεράσης (PCR). Ο προσδιορισμός της παρουσίας των πολυμορφισμών στο DNA πραγματοποιήθηκε με την χρήση ενζύμων περιορισμού. Συμπερασματικά, στις Ελληνίδες μετεμμηνοπαυσιακές γυναίκες με καρκίνο του μαστού υπό αγωγή με ταμοξιφαίνη, οι πολυμορφισμοί των οιστρογονικών υποδοχέων, δεν συνδέθηκαν, ούτε με την παρουσία παθολογίας του ενδομητρίου, ούτε με το στάδιο του καρκίνου του μαστού. / In postmenopausal women with estrogen receptor (ER) positive breast cancer, after surgical treatment long term tamoxifen administration has been proved beneficial. The aim of the present study was to identify whether these ER gene polymorphisms are associated with breast cancer stage or endometrial responsiveness to long-term tamoxifen treatment in postmenopausal women with breast cancer. The study included 87 postmenopausal women with estrogen receptor positive breast cancer treated with tamoxifen. The mean age of patients was 58,7 ± 4,7 years and the mean duration of Tamoxifen treatment was 3.9 ± 1,1 years. Genomic DNA was extracted from peripheral blood leukocyte samples by the standard phenol/chloroform procedure. Fragments of the ERα and ERβ genes encompassing the polymorphic sites were amplified by the polymerase chain reaction (PCR). The determination of presence of polymorphisms in the DNA was realised with restriction endonucleases. Ιn conclusion, in Greek postmenopausal women with breast cancer under tamoxifen treatment, Estrogen Receptors polymorphisms were not linked to either the presence of endometrial pathology or the stage of breast cancer.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2005. / Härtill 4 uppsatser.

Submitted by Verônica Esteves (vevenesteves@gmail.com) on 2018-01-11T14:41:24Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese Orlando Siqueira.pdf: 2924925 bytes, checksum: c32bce21e6c777f33da53c373787cb05 (MD5) / Approved for entry into archive by Verônica Esteves (vevenesteves@gmail.com) on 2018-01-11T14:41:40Z (GMT) No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese Orlando Siqueira.pdf: 2924925 bytes, checksum: c32bce21e6c777f33da53c373787cb05 (MD5) / Made available in DSpace on 2018-01-11T14:41:40Z (GMT). No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese Orlando Siqueira.pdf: 2924925 bytes, checksum: c32bce21e6c777f33da53c373787cb05 (MD5) Previous issue date: 2017 / Universidade Federal Fluminense. Hospital Universitário Antônio Pdro / Introdução: A anastomose término-terminal no tratamento da lesão das vias biliares durante a colecistectomia laparoscópica tem sido associada à formação de estenose. O objetivo deste estudo foi investigar experimentalmente o efeito do tratamento oral com tamoxifeno (tmx) sobre a fibrose, o colágeno e o transforming growth factor TGF-β1, - β2 e - β3 na anastomose da via biliar principal de porcos. Métodos: Vinte e seis porcos foram divididos em três grupos [sham (n = 8), controle (n = 9) e tmx (n = 9)]. Os ductos biliares foram seccionados e anastomosados nos grupos controle e tmx. Tmx (40 mg / dia) foi administrado oralmente ao grupo tmx, e os animais foram eutanasiados após 60 dias. A fibrose foi analisada pela coloração com tricromo de Masson. Picrosirius red foi utilizado para quantificar o teor total de colágeno e a proporção de colágeno tipo I / III. A expressão de mRNA do TGF-β1, -β2 e - β3 foi quantificada usando a reação em cadeia da polimerase em tempo real (qRT-PCR). Resultados: Os grupos de controle e estudo apresentaram fibrose maior do que o grupo sham, e o grupo de estudo apresentou fibrose menor do que o grupo controle (p = 0,011). Os grupos controle e tmx apresentaram maior teor total de colágeno do que o grupo sham (p = 0,003) e não houve diferença significativa entre os grupos controle e tmx. A proporção de colágeno tipo I / III foi maior no grupo controle do que nos grupos sham e tmx (p = 0,015) e não houve diferença significativa entre os grupos sham e tmx. Não houve diferenças significativas na expressão de mRNA de TGF-β1, -β2 e -β3 entre os grupos (p> 0,05). Conclusões: Tmx diminuiu a fibrose e impediu a alteração na proporção de colágeno tipo I / III causada pelo procedimento. / Introduction: End-to-end anastomosis in the treatment of bile duct injury during laparoscopic cholecystectomy has been associated with the formation of stenosis. The aim of this study was to experimentally investigate the effect of oral treatment with tamoxifen (tmx) on fibrosis, collagen and transforming growth factor TGF-β1, - β2 and – β3 on anastomosis of the common bile duct in pigs. Methods: Twenty-six pigs were divided into three groups (sham (n = 8), control (n = 9) and tmx (n = 9)). The bile ducts were sectioned and anastomosed in the control and tmx groups. Tmx (40 mg / day) was administered orally to the tmx group, and the animals were euthanized after 60 days. Fibrosis was analyzed by Masson's trichrome staining. Picrosirius red was used to quantify the total collagen content and the proportion of collagen type I / III. Expression of TGF-β1, -β2 and -β3 mRNA was quantified using the real-time polymerase chain reaction (qRT-PCR). Results: The control and study groups presented higher fibrosis than the sham group, and the study group had lower fibrosis than the control group (p = 0.011). The control and tmx groups presented higher total collagen content than the sham group (p = 0.003) and there was no significant difference between the control and tmx groups. The proportion of type I / III collagen was higher in the control group than in the sham and tmx groups (p = 0.015) and there was no significant difference between the sham and tmx groups. There were no significant differences in TGF-β1, -β2 and -β3 mRNA expression between the groups (p> 0.05). Conclusions: Tmx decreased fibrosis and prevented the change in the proportion of collagen type I / III caused by the procedure.

Philosophiae Doctor - PhD / Breast cancer is regarded as the most common cancer in South Africa and its rate of occurrence is increasing. About one in every 31 South African women are at the risk of developing breast cancer and early diagnosis and treatment guarantee 90% survival rate. Tamoxifen is the drugs of choice for the treatment of all stages of breast cancer. The drug binds with estrogen receptor (ER) to minimize the transcription of estrogen dependent genes. However, nearly 50% of ER-positive breast cancer patients either become resistant or fail to respond to tamoxifen resulting in a serious clinical challenge in breast cancer management. The Grand Health Challenges of South Africa includes the development of cost effective diagnostic systems suitable for early detection of diseases and drug resistivity for timely invention and better patient management. / 2020-08-31

Breast cancer, osteoporosis, and coronary heart disease (CHD) are three major threats to women’s health. Postmenopausal women with breast cancer are also at high risk for osteoporosis and CHD. Adjuvant tamoxifen therapy is not only an effective treatment for breast cancer, but has been shown to have a beneficial effect on bone and the cardiovascular system. Although tamoxifen has been convincingly demonstrated to be able to preserve bone mineral density (BMD), an unexpected increase of risk of fractures in patients treated with tamoxifen has been reported. The findings of the association of tamoxifen and CHD from previous studies were either borderline or inconsistent. To clarify the discrepancy between BMD and fractures and test the potential beneficial effect of tamoxifen on CHD, I conducted a series of retrospective studies in postmenopausal women with breast cancer who participated in the Cancer Surveillance in HMO Administrative Data (IMPACT study) or the Study of Osteoporotic Fractures (SOF). In patients who participated in the IMPACT study, I demonstrated that the association of tamoxifen and fracture incidence varied at different skeletal sites. Although the association of tamoxifen and fractures in the spine (HR=0.40, 95% CI: 0.09-1.85), wrist (HR=2.49, 95% CI: 0.88-7.06), and total body (HR=0.87, 95% CI: 0.49-1.55) was inconclusive, tamoxifen was associated with an apparent reduction of the risk of hip fracture (HR=0.41, 95% CI: 0.17-1.03, p=0.0565). Importantly, the pattern of observed association of tamoxifen with the risks of fractures among postmenopausal women with breast cancer is consistent with its widely reported preserving effect on bone mineral density. Using SOF data, I found that the association between BMD and fractures in women with breast cancer varied at different skeletal sites, and type of BMD measured. Non-specific BMD was not associated with hip fracture (HR=1.12; 95% CI: 0.78, 1.59). Site-specific BMD was more likely linked with hip fracture (HR=1.43, 95% CI: 0.99, 2.08) while change in BMD did not predict hip fracture (HR=1.05; 95% CI: 0.63, 1.72). The association of spine morphometric fracture with either non-specific or spine-specific BMD was similar (OR=1.40; 95% CI: 1.04, 1.90; OR=1.35, 95% CI: 0.99, 1.85, respectively). Overall, the association of BMD and fracture in elderly women with breast cancer is weak. Only site-specific BMD appears to have a consistently modest association with fractures in the corresponding skeletal sites. In the IMPACT study population, compared to patients without tamoxifen, the overall incidence of CHD in tamoxifen-treated patients was lower (adjusted HR=0.60, 95% CI: 0.40-0.88). For each year of tamoxifen use, there was a statistically significant decrease in the risk of CHD (HR=0.90, 95% CI: 0.82-0.98). Further analyses categorized by length of tamoxifen use showed that an apparent association with a decreased CHD risk was found in patients who received tamoxifen for two to five years (HR=0.54, 95% CI: 0.33-0.86). No association was detected after the discontinuation of tamoxifen therapy. In summary, I detected a possible benefit associated with tamoxifen on fractures in the hip, the most common fracture site. I also found that BMD did not predict osteoporotic fractures well in postmenopausal women with breast cancer. In addition, I demonstrated that tamoxifen was associated with a reduced risk of CHD in postmenopausal women with breast cancer in a dose-dependent manner. An apparent benefit was found in those patients who received tamoxifen therapy for at least two years.