Introduction: Osteoporosis belongs to multifactorial metabolic skeletal disease. The breast carcinoma is one of the most common malignities in women worldwide (with an exception of skin tumours). Postmenopausal women with non-metastatic breast carcinoma, which are treated with aromatase inhibitors (AI), have increased risk of developing osteoporosis. In these patients, it is necessary to identify the factors contributing to onset of osteoporosis which can be influenced, and take protective measures towards bone metabolism, in order to reduce the occurrence of serious low-traumatic fractures. Objective: The objective of this thesis is to evaluate the diet with regard to risk factors leading to osteoporosis and bone fractures in postmenopausal women with breast carcinoma without metastases, which are treated with AI. Another objective for this group of women is to evaluate the changes of bone mineral density (BMD) and certain parameters of body composition during long-term treatment of AI. Methods: The present study is based on a questionnaire containing a table to quote a three day diet, which was subsequently analysed to identify the overall energetic income, the income of proteins, fat, carbohydrates, dietary fibre and calcium. The supply of vitamin D was deduced for the serum concentration of...

A breast cancer cell line stably transfected with the CYP19 gene had been employed for aromatase inhibition. Among the phytochemicals tested, the major dietary flavonoids, such as genistein and daidzein, produced very weak inhibition. On the other hand, the red clover isoflavone biochanin A, the hydroxychalcone butein and the red grape phytoalexin resveratrol were found to be effective aromatase inhibitors. Cell proliferation assay had shown that they could inhibit ER-positive cell proliferation induced by testosterone, and the inhibitory effect was specifically attributed to the reduction of estrogen synthesis. In another breast cancer cell line SK-BR-3, resveratrol, biochanin A and genistein inhibited CYP19 both in enzyme and promoter I.3/II transcriptional levels. The element responsible for the inhibition of aromatase by these phytoestrogens should fall within the region between -556 to -446 by upstream of exon II. / Breast cancer is one of the most common cancers affecting women. Estrogen plays an important role in breast cancer initiation and development. The majority of breast tumors are initially dependent upon estrogen to support their growth. Most breast cancers occur in the postmenopausal period. However, the intra-tumoral estradiol (E2) is maintained at a high level equivalent to the pre-menopausal status. High intra-tumoral E2 level in postmenopausal women is sustained by the biosynthesis of estrogens in the tumorous tissue. / Genistein and Biochanin A, ranged from 0.1 to 10 muM, might act as estrogen agonist and induced aromatase activity and promoter I.1 transactivation in ERalpha-transfected SK-BR-3 cells. (Abstract shortened by UMI.) / The aromatase enzyme, CYP19, belongs to a family of P450 enzyme. As a final rate-limiting step in estrogen biosynthesis, it catalyzes the conversion of C 19 steroids to estrogens. The expression of CYP19 is tissue-specific, and is regulated by alternate promoter usage. The use of aromatase inhibitors for breast cancer treatment has become a major therapeutic approach. / The consumption of some phytochemicals protects against breast cancer. Yet the mechanisms are far from clear. In my present study, various phytochemicals, including phytoestrogens, monoterpenes and carotenoids, were evaluated for their effect on aromatase. / Wang Yun. / "July 2005." / Adviser: Lai-Kwok Leung. / Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3716. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 145-169). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract in English and Chinese. / School code: 1307.

Les formes orales de traitements anticancéreux se sont considérablement développées récemment. La question de l’adhésion au traitement devient donc un nouvel enjeu en oncologie. Cette thèse aborde de façon générale le problème de l’adhésion aux traitements oraux en oncologie, et plus spécifiquement celui de la mesure en bases de données médico-administrativesde l’observance et de la persistance à l’hormonothérapie, traitement oral majeur dans le cancer du sein. Le point de vue retenu est celui de la pharmacoépidémiologie, à savoir l’étude des consommations pharmaceutiques en contexte clinique. La première partie de cette thèse fait le point sur les connaissances actuelles concernant l’adhésion à l’hormonothérapie - tamoxifène et inhibiteurs de l’aromatase (IA) - dans le cancer du sein. La seconde partie, reposant sur l’analyse de cohortes de patientes atteintes de cancer du sein sélectionnées à partir de (1) la UK General Practice Research Database et (2) des données de l’Assurance Maladie, a montré que : - Plus de la moitié des femmes de moins de 40 ans au diagnostic ne reçoivent plus de tamoxifène à 5 ans. Il s’agit du groupe de femmes le plus à risque d’arrêt prématuré de traitement. - Chez les femmes âgées de plus de 50 ans au diagnostic, les arrêts de traitement sont moins fréquents pour les IA que pour le tamoxifène. - Les déterminants associés à la non-persistance sont un faible soutien social et la déclaration précoce de non-prise de traitement par la patiente chez les femmes jeunes. Chez les femmes âgées, l’utilisation de médecines complémentaires et alternatives, la présence de comorbidités sont associées à une augmentation du risque d’arrêt de traitement. A contrario, la présence d’une poly-médication est associée à une diminution du risque d’arrêt.- Dans les études précédentes, une proportion importante de femmes reprend son traitement au moins une fois après l’avoir arrêté de façon prolongée. Les arrêts transitoires de traitements ont été pris en compte à l’aide de modèles multi-états. La probabilité d’arrêt de traitement estimée à partir de ces modèles est plus faible que celle mesurée par la méthode de Kaplan-Meier, après la première année de traitement. La non-adhésion à l’hormonothérapie est fréquente. Certains de ses déterminants sont modifiables ou peuvent servir à identifier précocement les patientes à risque de non-observance. La prise en compte des arrêts transitoires de traitement est importante dans la mesure de la persistance. L’adhésion est l’élément clé faisant le lien entre l’efficacité d’un traitement mesuréedans un essai clinique et son impact dans la vraie vie. Il est urgent de prendre conscience de l’importance de la non-adhésion des formes orales en oncologie / The use of oral anticancer therapies has significantly increased in recent years. Adherence to these therapies has therefore become a major issue in the field of oncology. This thesis focuses on the question of treatment adherence in oncology, and more specifically on the use of medical records and administrative databases to estimate adherence and persistence to hormonal therapy—now a major form of oral breast cancer therapy. Our perspective is based on pharmacoepidemiology, i.e. the study of drugs in a clinical setting. The first part of this thesis synthesizes current knowledge on adherence and persistence to hormonal therapy for BC – i.e. tamoxifen and aromatase inhibitor therapies.The second part, which is based on the study of two cohorts constituted (1) from the UK General Practice Research Database and (2) from the French National Health Insurance System, demonstrates that - More than half of women younger than 40 at diagnosis do not receive any tamoxifen at 5years of follow-up. This group of women presents the highest rates of treatmentinterruption. - Among women over 50 at diagnosis, those receiving some form of AI therapy discontinue less frequently than those on tamoxifen treatment. - Determinants of non-persistence identified in the studies under review include low social support and self-reporting of non-compliance among younger women. Among older women, those using complementary or alternative medicine or suffering from comorbidities are more likely to discontinue their treatment, whereas women usingpolypharmacy are less likely to discontinue. - In previous studies, a large proportion of women who discontinued their treatment resumed after a prolonged gap. To account for these temporary treatment discontinuations, we used multi-state models. The probability of being off treatment estimated from these models is lower than that estimated from Kaplan-Meier estimates, after the 1st year of treatment. Adherence to hormonal therapy is largely suboptimal. Some of its determinants are modifiablefactors, while others can be used to identify sub-groups of patients at high risk of non-adherence. Accounting for temporary treatment discontinuation is important when measuring nonpersistence. Adherence is a key element for the translation of efficacy measured in clinical trials into effectiveness in real life. There is an urgent need to acknowledge the problem of nonadherence to oral therapy in oncology

Na avicultura industrial, diferenças no desempenho zootecnico de machos e femeas de linhagens pesadas forcam o setor a alojar separadamente os sexos com o propósito de facilitar manejo, uniformizar lotes, reduzir custos e otimizar a producao. Desse modo, meios que reduzam ou eliminem a disparidade entre sexos no ambito zootecnico podem resultar em ganhos gerenciais e econômicos no mercado avicola. A masculinizacao de femeas objetivando aproximar sua performance aquela manifestada por machos pode ser considerado um recurso interessante. Sendo assim a aplicacao de inibidores ou bloqueadores da aromatase P450 durante o desenvolvimento embrionario pode induzir graus variados de masculinizacao das femeas sem a utilizacao de protocolos hormonais, em um fenomeno chamado reversao sexual. Assim, os objetivos desse projeto foram: (1) comparar a acao de inibidores de aromatase de terceira geracao (Droga B e droga C) em relacao ao fadrozole (farmaco amplamente citado em literatura) sobre a taxa e o grau de reversao sexual em frangas de corte; e (2) estimar o impacto desses tratamentos sobre parametros de incubacao (mortalidade embrionaria e eclodibilidade) e indices zootecnicos (peso ao nascer, ganho de peso, conversao alimentar e peso final aos 42 dias). Os resultados, deste estudo, mostraram que o inibidor de aromatase droga B obteve maior proporção machos quando comparado aos outros IAs testados. Contudo, quando avaliamos as aves tratadas por este fármaco, em relação aos índices zootécnicos, estas apresentaram resultados similares ao grupo misto e inferior quando comparadas aos machos genéticos. Na sexagem morfológica aos 42 dias de idade foi observado que no grupo tratado com a droga B, 58% das aves apresentavam ovário ou ovostestis ao invés de testículos o que impactou negativamente no ganho de peso deste grupo. / Performance diferences between male and female broilers compel the poultry industry to rear sexes separately in order to favor management, uniform flocks, reduce costs and optimize production. Notwithstanding, this practice has logistical implications that create additional expenses, and in some cases, broiler companies encounter producer preferences for a particular sex due to its productive traits. Thus, methods that reduce or eliminate gender disparity in meat production efficiency can result in operational and economical benefits to poultry market. Masculinization of females aiming to bring performance closer to those expressed by males may be viewed as an interesting alternative. Therefore, the application of aromatase inhibitors or blockers during embryonic development can induce varying degrees of female masculinization without the use of hormonal protocols, in a process called sex reversal. Therefore, our objectives herein were: (1) to compare the action of third generation aromatase inhibitors (Drug B and Drug D) in relation to fadrozole (a drug widely used in literature) on the rate and degree of sexual reversal in broiler pullets; and (2) to estimate the impact of these treatments on incubation (embryonic mortality and hatchability) and performance parameters (birth weight, weight gain, feed conversion and final weight at 42 days). The results, from this study, showed that the aromatase inhibitor drug B obtained a higher rate of sexual reversion when compared to the other AIs tested. However, when we evaluated the birds treated by this drug, in relation to the zootechnical indexes, these presented similar results to the mixed and inferior group when compared to the genetic males. In the morphological sexing at 42 days of age, it was observed that in the group treated with AI, 58% of the birds presented ovary or ovostestis instead of testicles, which impacted the weight gain of this group.

Orientador: João Francisco Marques Neto / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T02:25:05Z (GMT). No. of bitstreams: 1 Bartmann_AnaKarina_D.pdf: 1744066 bytes, checksum: d1f26d98092af3615052cb779daf0acc (MD5) Previous issue date: 2012 / Resumo: Introdução: O uso de inibidores de aromatase para o tratamento de longo prazo de pacientes com câncer de mama com receptores hormonais positivos tem sido considerado uma boa maneira de controlar a doença em termos de recorrência e metástases. Infelizmente, no entanto, os inibidores de aromatase podem reduzir drasticamente a massa óssea mineral. Devido a este fato, hoje em dia tem sido considerado de extrema importância a realização de exames complementares para a avaliação do status ósseo como marcadores do metabolismo ósseo e densitometrias ósseas. A vitamina D é de especial interesse em termos de câncer, uma vez que poderia ser bom preditor do desenvolvimento não só da osteoporose, mas também de eventual recorrência tumoral. Material e Métodos: A fim de verificar a relação entre a densidade mineral óssea (DMO) e valores de vitamina D foram avaliados níveis de vitamina D e cálcio no sangue, além de densitometrias ósseas e calciúria de 24 horas de 147 pacientes com diagnóstico de câncer de mama - 80 pacientes em uso de inibidores da aromatase e 67 pacientes em uso de tamoxifeno (grupo controle). As pacientes foram estratificadas por tempo de utilização da medicação: <1 ano, 1-2 anos, 2-3 anos, 3-4 anos e 4-5 anos. Vinte e um pacientes com baixa densidade mineral óssea e os valores baixos de vitamina D sérica foram tratadas com suplementação oral de 800 UI/dia de vitamina D durante 1 ano. Os valores de DMO, antes e depois do tratamento, foram comparados. Resultados: Os usuários de inibidores de aromatase apresentaram menor densidade mineral óssea (p = 0,0162 valor), bem como níveis mais baixos de vitamina D (p = 0,0001) em comparação ao grupo controle. Os grupos apresentaram valores de correlação distintos para as variáveis vitamina D e BMD. Como esperado, o grupo controle apresentou uma correlação positiva (r = 0,633 com p-valor = 0,000). O grupo de utilizadores inibidores de aromatase apresentou um coeficiente de correlação baixa (r = 0,287, com valor de p = 0,01), o qual foi explicado por uma maior diminuição dos valores de vitamina D no tempo quando comparado à diminuição na densidade mineral óssea. Finalmente, notamos uma diferença significativa entre valores de DMO antes e depois de um ano de tratamento com vitamina D. Conclusão: Os resultados permitem sugerir que mulheres em tratamento com inibidores de aromatase que têm baixos níveis de vitamina D devem receber suplementos de vitamina D ainda que apresentem ou não osteoporose e/ou osteopenia / Abstract: Introduction: The use of aromatase inhibitors for long term treatment of patients with positive hormonal receptors breast cancer has been considered a good way to control the disease in terms of recurrence and local/ distant metastasis. Unfortunately however, aromatase inhibitors can reduce severely the mineral bone mass. Because of this fact, nowadays it has been considered of utmost importance to perform bone densitometries and collect samples of blood bone quality markers in the follow up of these patients. Vitamin D is of special interest in terms of cancer, since it could be good predictor of the development not only of osteoporosis but also of bone metastasis and tumoral recurrence in the breast. Material and Methods: We compared levels of blood vitamin D and bone mineral density of 80 patients using aromatase inhibitors and 67 patients using tamoxifen (control group) in order to verify the relation between both variables. Patients were stratified by time of medication use: <1 year, 1-2 years, 2-3 years, 3-4 years and 4-5 years. Twenty-one patients with low BMD and similarly low values of blood vitamin D were treated with oral vitamin D supplementation 800 IU per day dose for 1 year. Values of BMD before and after treatment were compared. Results: Aromatase inhibitors users have smaller BMD (p value = 0.0162) as well as lower levels of vitamin D (p value = 0.0001) in comparison to the control group. Groups presented distinct correlation values for the variables vitamin D and BMD. As expected, the control group showed a significant correlation (r = 0.633 with p-value = 0.000). The group of aromatase inhibitors users presented a low correlation coefficient (r = 0.287 with p-value = 0.01), which was explained by a greater decrease in the values of vitamin D in time when compared to the decrease in BMD. Finally we notice a significant difference between BMD values before and after one-year treatment with vitamin D. Conclusion: We suggest that women in treatment with aromatase inhibitors who have low vitamin D levels receive dietary supplements of it, whether or not they have osteopenia or osteoporosis. Despite the fact that there is no protocol for breast cancer prevention with dietary supplements of vitamin D, we also suggest that women with high risk for breast cancer should undergo blood measurements of vitamin D and receive supplements if blood samples show low levels of it / Doutorado / Clinica Medica / Doutora em Clínica Médica

Indiana University-Purdue University Indianapolis (IUPUI) / Breast cancer remains the most prevalent malignancy diagnosed in women. More than two thirds of all diagnosed breast cancers are estrogen receptor (ER)-positive and are dependent on estrogen signaling. Drugs for the treatment of ER-positive breast cancer can be divided into three classes: selective estrogen receptor modulators (SERMs), selective estrogen receptor down-regulators (SERDs) and aromatase inhibitors (AIs). However, the efficacy and safety of SERMs, SERDs and AIs are compromised by side effects or tumor resistance. One possible way of improving treatment efficacy and safety profiles is to develop agents with dual aromatase inhibitory and ER modulatory activity. Over the past 30 years, tamoxifen, a SERM, has become the most widely used drug for the adjuvant treatment of breast cancer. The metabolism of tamoxifen has a complex profile involving both active and inactive metabolites, among which endoxifen, 4-hydroxytamoxifen (4-HT) and norendoxifen (Nor) have been shown to have ER modulatory activity. Previous studies have also shown that norendoxifen is a potent AI in vitro. These preliminary studies support the utilization of tamoxifen metabolites as lead compounds for the development of dual AI/SERM(D) agents. Hydroxynorendoxifen (Hdn) was identified as a novel tamoxifen metabolite, with an average plasma concentration of 0.82 nM. Nor and Hdn were potent and relatively selective AIs, with Kis of 70 nM and 20 nM, respectively. Nor and Hdn have high binding affinity for ER-α and ER-β, with EC50 values less than 35 nM. Nor and Hdn can inhibit breast cancer cell proliferation with high potency, with IG50s of 25 nM and 9 nM, respectively. Nor and Hdn can suppress progesterone receptor (PGR) mRNA expression level by reducing it by 68% and 86%. Moreover, a series of Nor analogues were shown to have both potent aromatase inhibitory activity and high ERs binding affinity. Results from this dissertation will contribute to three aspects: 1) the identification of Hdn as a tamoxifen metabolite illustrated a more comprehensive metabolism profile of tamoxifen; 2) the data suggest Nor and Hdn possess dual aromatase inhibitory and ER antagonistic activity; 3) a series of Nor analogues were characterized as lead compounds for the development of dual AI/SERM(D) agents.

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Made available in DSpace on 2014-12-17T14:16:38Z (GMT). No. of bitstreams: 1 RandRM.pdf: 491733 bytes, checksum: 93fd5e529dea72386495c9d4b3d94d8f (MD5) Previous issue date: 2006-08-18 / Hormone therapy is an important tool in the treatment of breast cancer and tamoxifen represents one of the most important drugs used in this type of treatment. Recently other drugs based on the inhibition of aromatase had been developed, this enzyme is responsible for the synthesis of estrogenic esteroids from the androgenic ones. The objective of this study would be the development of a quantitative cytological model of murine estral analysis that allowed the characterization of different hormone drugs effect over vaginal epithelium. The technique of monochromatic staining with Evans blue (C.I. 23860) showed to be efficient in the qualitative and quantitative classification of the cycle. It had been observed differences in the cytological standard of animals submitted to the studied drugs; tamoxifen presented a widening of phases of lesser maturation (diestrais), while anastrozole and exemestane increased the duration of the phases of larger maturation (estrais). The data were analysed through a cubical non linear regression (spline) which allowed a better characterization of the drugs, suggesting a proper cytological profile to the antagonism of the estrogen receptor (tamoxifen), aromatase competition (anastrozole) and inhibition of the enzyme (exemestane) / A hormonioterapia ? um importante recurso no tratamento do c?ncer de mama e o tamoxifeno representa o f?rmaco mais empregado neste tipo de tratamento. Recentemente foram desenvolvidos outros f?rmacos baseados na inibi??o da aromatase, enzima respons?vel pela s?ntese de ester?ides estrog?nicos a partir de androg?nios. O objetivo deste estudo seria o desenvolvimento de um modelo citol?gico quantitativo de analise estral murina que permitisse a caracteriza??o dos efeitos farmacol?gicos de diferentes hormonioter?picos sob epit?lio vaginal. A t?cnica de colora??o monocrom?tica com Azul de Evans (C.I. 23860) mostrou-se eficaz na classifica??o qualitativa e quantitativa do ciclo. Observou-se diferen?as no padr?o citol?gico de animais submetidos aos f?rmacos em estudo; onde o tamoxifeno apresentou alargamento das fases de menor matura??o (diestrais), enquanto que o anastrozol e o exemestano incrementaram a dura??o das fases de maior matura??o (estrais). O tratamento dos dados atrav?s de uma regress?o n?o linear por spline c?bica permitiu melhor caracteriza??o dos f?rmacos, sugerindo um perfil citol?gico pr?prio ao antagonismo do receptor de estr?geno (tamoxifeno), competi??o da aromatase (anastrozol) e inibi??o da enzima (exemestano)

<p>U ovoj doktorskoj disertaciji&nbsp; razvijen&nbsp; je fluorescentni test u kvascu za identifikaciju potencijalnih prirodnih ili sintetičkih liganada&nbsp; ER&alpha;, ER&beta; ili AR i kvantifikaciju&nbsp; njihovog&nbsp; afiniteta&nbsp; vezivanja sa mogućno&scaron;ću testiranja čitavih biblioteka modifikovanih steroida i ksenoestrogena. Takođe, opisana&nbsp; je primena optimizovanog biosenzora&nbsp; za&nbsp; procenu&nbsp; estrogenog&nbsp; potencijala sintetskih steroida i odabranih biljnih ekstrakata bogatih jedinjenjima fitoestrogenih osobina. U cilju potpunijeg sagledavanja mehanizma&nbsp; delovanja&nbsp; odabranih&nbsp; modifikovanih&nbsp; steroida&nbsp; ispitana&nbsp; je&nbsp; njihova antiproliferativna aktivnost prema ćelijskim&nbsp; linijama estrogen receptor pozitivnog kancera dojke&nbsp; (MCF-7) i kancera prostate (PC-3), dok su&nbsp; in silico metodom molekularnog&nbsp; dokinga&nbsp; predviđene&nbsp; energije&nbsp; i&nbsp; geometrije&nbsp; vezivanja&nbsp; ovih&nbsp; jedinjenja za ligand-vezujuće&nbsp; domene&nbsp; ER&alpha; i ER&beta;. Drugi deo ovog rada obuhvata razvoj testa za&nbsp; ispitivanje aktivnosti humanog enzima aromataze,&nbsp; heterologno eksprimiranog u ćelijama&nbsp; kvasca&nbsp; Saccharomyces cerevisiae&nbsp; i/ili&nbsp; bakterija Escherichia coli, u prisustvu&nbsp; ili&nbsp; odsustvu&nbsp; inhibitora.&nbsp; Interakcije modifikovanih&nbsp; steroida, odabranih na osnovu strukture,&nbsp; sa&nbsp; aromatazom&nbsp; ispitane&nbsp; su&nbsp; osetljivim spektroskopskim metodama, praćenjem promene spinskog stanja Fe iz hem grupe ili promene fluorescencije ostatka&nbsp; triptofana&nbsp; iz&nbsp; aktivnog&nbsp; centra usled konformacione&nbsp; promene&nbsp; proteina, izazvane interakcijom sa ligandom. Razvijeni in vitro testovi bez upotrebe radioaktivnih izotopa su, osim&nbsp; visoke efikasnosti&nbsp; i&nbsp; bezbednosti&nbsp; po&nbsp; korisnika&nbsp; i&nbsp; okolinu, pokazali&nbsp; specifičnost&nbsp; i&nbsp; ekonomičnost&nbsp; u preliminarnom&nbsp; skriningu&nbsp; liganada&nbsp; steroidnih receptora&nbsp; i inhibitora aromataze. Jedinjenja&nbsp; kod kojih je detektovana&nbsp; značajna biolo&scaron;ka aktivnost mogu potencijalno poslužiti kao osnova za razvoj terapeutika u lečenju hormon-zavisnih bolesti i stanja, koja danas predstavljaju globalni zdravstveni problem.</p> / <p>In&nbsp; this&nbsp; doctoral&nbsp; dissertation,&nbsp; a&nbsp; fluorescent&nbsp; assay&nbsp; in&nbsp; yeast&nbsp; was&nbsp; developed&nbsp; for&nbsp; identification&nbsp; of&nbsp; potential&nbsp; natural or synthetic ligands of ER&alpha;, ER&beta; or AR and<br />quantification&nbsp; of&nbsp; their&nbsp; binding&nbsp; affinity,&nbsp; as&nbsp; well&nbsp; asevaluation&nbsp; of&nbsp; the&nbsp; estrogenic&nbsp; potential&nbsp; of&nbsp; synthetic steroids&nbsp; and&nbsp; selected&nbsp; plant&nbsp; extracts&nbsp; rich&nbsp; in phytoestrogen&nbsp; content.&nbsp; The&nbsp; assay&nbsp; could&nbsp; be&nbsp; used&nbsp; to&nbsp; screen&nbsp; libraries&nbsp; of&nbsp; modified&nbsp; steroids&nbsp; and xenoestrogens.&nbsp; In&nbsp; order&nbsp; to&nbsp; better&nbsp; understand&nbsp; the biomedical&nbsp; potential&nbsp; of&nbsp; selected&nbsp; modified&nbsp; steroids, results&nbsp; were&nbsp; compared&nbsp; to&nbsp; antiproliferative&nbsp; activity against&nbsp; estrogen&nbsp; receptor&nbsp; positive&nbsp; breast&nbsp; cancer (MCF-7)&nbsp; and&nbsp; prostate&nbsp; cancer&nbsp; (PC-3)&nbsp; cell&nbsp; lines. Binding&nbsp; energies&nbsp; and&nbsp; the&nbsp; geometry&nbsp; of&nbsp; binding&nbsp; of these&nbsp; compounds&nbsp; for&nbsp; ER&alpha;&nbsp; and&nbsp; ER&beta;&nbsp; ligand&nbsp; binding domains&nbsp; were&nbsp; predicted&nbsp; in&nbsp; silico&nbsp; by&nbsp; molecular&nbsp; docking&nbsp; methods.&nbsp; The&nbsp; second&nbsp; part&nbsp; of&nbsp; this&nbsp; study includes development&nbsp; of&nbsp; an&nbsp; assay&nbsp; for&nbsp; study&nbsp; of&nbsp; aromatase&nbsp; activity&nbsp; in&nbsp; the&nbsp; presence&nbsp; or&nbsp; absence&nbsp; of inhibitors&nbsp; by&nbsp; heterologous&nbsp; expression&nbsp; of&nbsp; human aromatase&nbsp; in&nbsp; Saccharomyces&nbsp; cerevisiae&nbsp; and/or Escherichia&nbsp; coli&nbsp; cells,&nbsp; as&nbsp; model-organisms. Furthermore, interactions between modified steroids, selected&nbsp; according&nbsp; to&nbsp; their&nbsp; structure,&nbsp; and&nbsp; aromatase were&nbsp; tested&nbsp; using&nbsp; sensitive&nbsp; spectroscopic&nbsp; methods based on ligand-induced changes&nbsp; in&nbsp; the&nbsp; spin state of Fe&nbsp; from&nbsp; the&nbsp; heme&nbsp; group&nbsp; or&nbsp; changes&nbsp; in&nbsp; the fluorescence&nbsp; of&nbsp; a&nbsp; tryptophan&nbsp; residue&nbsp; in&nbsp; the&nbsp; active site.&nbsp; The&nbsp; non-radioactive&nbsp; in&nbsp; vitro&nbsp; assays&nbsp; developed&nbsp; here, besides high efficiency, user and environmental safety,&nbsp; also&nbsp; have&nbsp; greater&nbsp; specificity&nbsp; and&nbsp; are&nbsp; more cost-effective&nbsp; for&nbsp; preliminary&nbsp; screening&nbsp; of&nbsp; steroid receptor&nbsp; ligands&nbsp; and&nbsp; aromatase&nbsp; inhibitors. Additionally,&nbsp; compounds&nbsp; identified&nbsp; to&nbsp; express significant biological activity can serve as a basis for the&nbsp; development&nbsp; of&nbsp; potential&nbsp; therapeutics&nbsp; in&nbsp; the treatment&nbsp; of&nbsp; hormone-dependent&nbsp; diseases&nbsp; and conditions, a global health issue today.</p>

Indiana University-Purdue University Indianapolis (IUPUI) / Aromatase inhibitors (AIs) are the current standard of care for the treatment of hormone receptor positive breast cancer in postmenopausal women. Nearly one-half of patients receiving AI therapy develop musculoskeletal toxicity that is characterized by joint and/or muscle pain and approximately one-fourth of patients discontinue their therapy as a result of musculoskeletal pain. Since there are no effective strategies for prevention or treatment, insight into the mechanisms of AI-induced pain is critical to improve treatment. However, there are few studies of AI effects in animal models of nociception. To determine whether AIs produce hypersensitivity in animal models of pain, I examined the effects of AI administration on mechanical, thermal, and chemical sensitivity in rats. The results demonstrate that (1) repeated injection of 5 mg/kg letrozole in male rats produces mechanical, but not thermal, hypersensitivity that extinguishes when drug dosing is stopped; (2) administering a single dose of 1 or 5 mg/kg letrozole in ovariectomized (OVX) rats also induces mechanical hypersensitivity, without altering thermal sensitivity and (3) a single dose of 5 mg/kg letrozole or daily dosing of letrozole or exemestane in male rats augments flinching behavior induced by intraplantar ATP injection. To determine whether the effects of AIs on nociceptive behaviors are mediated by activation or sensitization of peptidergic sensory neurons, I determined whether letrozole exposure alters release of calcitonin gene-related peptide (CGRP) from isolated rat sensory neurons and from sensory nerve endings in rat spinal cord slices. No changes in basal, capsaicin-evoked or high extracellular potassium-evoked CGRP release were observed in sensory neuronal cultures acutely or chronically exposed to letrozole. Furthermore, letrozole exposure did not alter the ability of ATP to augment CGRP release from sensory neurons in culture. Finally, chronic letrozole treatment did not augment neuropeptide release from spinal cord slices. Taken together, these results do not support altered release of this neuropeptide into the spinal cord as mediator of letrozole-induced mechanical hypersensitivity and suggest the involvement of other mechanisms. Results from this dissertation provide a new experimental model for AI-induced hypersensitivity that could be beneficial in delineating mechanisms mediating pain during AI therapy.