A. Cano Sanchez J. Calaf i Alsina J.-L. Dueñas-Díez. Selective Estrogen Receptor Modulators. A New Brand of Multitarget Drugs

Transcription

1 A. Cano Sanchez J. Calaf i Alsina J.-L. Dueñas-Díez Selective Estrogen Receptor Modulators A New Brand of Multitarget Drugs

2 Antonio Cano Sanchez Joaquim Calaf i Alsina José-Luis Dueñas-Díez (Editors) Selective Estrogen Receptor Modulators A New Brand of Multitarget Drugs With 74 Figures, Including 40 in Color 123

3 Antonio Cano Sanchez Department of Pediatrics Obstetrics and Gynecology University of Valencia Valencia, Spain Joaquim Calaf i Alsina Servei d Obstetricia i Ginecologia Hospital de la Santa Creu i Sant Pau C/ Sant Antoni M. Claret Barcelona jcalaf@santpau.es José-Luis Dueñas-Díez University of Sevilla Department of Obstetrics and Gynaecology Hospital Universitario Virgen Macarena Sevilla, Spain Library of Congress Control Number: ISBN Springer Berlin Heidelberg New York ISBN Springer Berlin Heidelberg New York This work is subject to copyright. All rights reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable for prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media springeronline.com Springer-Verlag Berlin Heidelberg 2006 Printed in Germany The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Editor: Dr. Ute Heilmann, Heidelberg Desk Editor: Wilma McHugh, Heidelberg Cover design: Frido Steinen-Broo, estudio Calamar, Spain Typesetting and production: LE-TEX Jelonek, Schmidt & Vöckler GbR, Leipzig, Germany Printed on acid-free paper 21/3100/YL

4 Preface The increasing awareness on the varied consequences of hypogonadism in distinct organs and systems has supported the notion of estrogens as systemic agents. This observation is congruent with the variety of tissues affected by estrogens when used in hormone therapy formulations on hypogonadic women. Apart from the genital tract and the breast, recognized as traditional targets for estrogens, the skeleton, the vascular tree, or the central nervous system, are good examples of territories that have demonstrated sensitivity to estrogens. This evidence has created great interest, as shown by the great amount of literature that has been produced on the benefits and risks associated with the use of estrogens. In parallel to the clinical interest, basic research has improved our knowledge on the complexities involved in estrogen action at the molecular level. Together with effects mediated through specific receptors, a concept that has been the mainstay of the interpretation of estrogen action for years, there is enough evidence to hold the notion of receptor-independent effects. The substantial advances in modern technology applied to research have helped in enlightening the particulars of this versatile action of estrogens. This more detailed knowledge on the sophisticated mechanism of action of estrogens has nourished the emergence of multiple hypotheses speculating with the possibility of manipulating estrogen action. The notion that a widely extended regulatory system of cell function, as it is the estrogen receptor machinery, might be modulated at wish has arisen as an attractive, although still elusive postulate. Increasing support for this concept has evolved from the developments of classical pharmacology in the field of agonists/antagonists for receptors, together with the extensive basic and clinical knowledge acquired with the use of tamoxifen, originally considered as an estrogen receptor antagonist. It has been the great experience with tamoxifen, plus the accompanying basic research, which have led to the actual notion that tamoxifen is, as perhaps any compound capable of binding to the estrogen receptor, nothing but a selective estrogen receptor modulator (SERM). Today, the biological steps set in motion by the activation of the estrogen receptor are sufficiently intricate to convert

5 VI Preface into a difficult exercise the definition of compounds that respond to the concept of pure agonism or antagonism. Instead, it seems that there is a wide, increasing variety of ligands capable of binding to distinct species of receptors and determining effects whose profile will depend on the compound as well as on the target tissue. The corollary of these premises is that modern medicine faces a great challenge but at the same time a wonderful opportunity. The hypothesis of governing a physiological, an often powerful, regulatory system of cellular functions is starting to become a tangible reality. Accordingly, the new concept of multitarget drugs has been created. From the veteran tamoxifen, which proved efficacious as an antagonist in breast but created concern due to its agonistic effects in the uterus, the list of SERMs has not interrupted its continuous growth. Raloxifene has defined a landmark in this sequence as a consequence of the abundant basic and clinical studies forming a solid body of doctrine that warrants his actual indication in osteoporosis as well as its possible role as chemopreventive against breast cancer. Many other SERMs, distributed in different families, are already under research in experimental and clinical studies. This book represents the effort of a group of scientists and clinicians to offer the reader an updated view of the main advances occurred in the field in the recent years. Every author has been selected because of his/her experience with modulators of estrogen receptors, either in basic or clinical grounds. This explains the structure of the book, which reviews the main basic concepts in the first part, to immediately concentrate in the recent news on the many uses of SERMs in clinical practice. We are very grateful with all of them for his excellent contribution. To conclude, we also would like to express our gratitude to Springer-Verlag for the excellent technical support as well as to those who, from different perspectives, are at the base of our work, our patients and our families. Antonio Cano Joaquin Calaf José-Luis Dueñas-Díez

6 Contents Part I Basic Area 1 Molecular Mechanisms of Estrogen Action in Target Tissues B. Nicolás Díaz Chico, Domingo Navarro Bosch, Juan C. Díaz Chico, Eduardo Escrich Escriche Introduction GeneralAspects The Discovery of Hormone Receptors for Steroid Hormones NuclearHormoneReceptors? StructureofEstrogenReceptors PrimaryStructureofEstrogenReceptors Activity Domains in the Molecules of Estrogen Receptors GeneticEncodingofEstrogenReceptors NativeReceptor EstrogenTransformstheNativeReceptor DomainofNuclearLocation Hormone ReceptorInteraction LigandBindingDomain StructureofReceptorandHormonalAntagonism ReceptorFoldinginSeparateDomains DimerizationDomains Receptor GenomeInteraction SpecificDNASequencesfortheHormoneResponse DNA-BindingDomain RecognitionofHormoneResponseElement RoleofReceptor HormoneResponseElementComplex HormonalRegulationofGeneTranscription DomainsofTranscriptionActivation(Transactivators) IntermediaryTranscriptionCofactors InteractionofReceptorwithTranscriptionCofactors CoactivatorsinCellularandGenePromoterContext ConceptofSERMfromPointofViewofCoactivator... 29

7 VIII Contents StructureofChromatinandHormoneResponse Specificity of Gene Transcription Induced by Hormones MultipleRegulationofGeneExpression Nuclear Hormone Receptors and Endocrine Disruptors RegulationofIntensityofHormoneResponse MembraneReceptorsforSteroidHormones RegulationofConcentrationofReceptorsperCell ReceptorDestinyAfterActivation Cross-TalkSignaling SilencingofGenesforNuclearHormoneReceptors Summary References Clinical Pharmacology of Selective Estrogen Receptor Modulators (SERMs) Fernando Marín, M a Carmen Barbancho Introduction Classification Pharmacological Characteristics of SERMs Triphenylethylenes Benzothiophenes Naphthalenes Indoles Benzopyrans Conclusions References Action of Selective Estrogen Receptor Modulators (SERMs) Through the Classical Mechanism of Estrogen Action Fernando Marín, M a Carmen Barbancho Introduction EstrogenReceptorSubtypes ConformationofLigand ERComplex Coregulator Protein Cell Content andcoactivators/corepressorsratio Transrepression: Regulation of Gene Expression by an ERE-Independent Mechanism References... 76

8 Contents IX 4 Cellular and Molecular Basis for Acute Nongenomically Mediated Actions of SERMs Mario Díaz, Jorge Marrero-Alonso, Benito García Marrero, Raquel Marín, Tomás Gomez, Rafael Alonso Introduction CellularandMolecularTargetsforRapidActions Interaction with Ion Channels MultidrugResistanceandP-glycoprotein SignallingTransducers Lipids,MembraneLipids,andFluidity Specific Antiestrogen-Binding Sites (AEBS) FinalConsiderations References The Hypothalamus Pituitary Ovarian Axis as a Model System for the Study of SERM Effects: An Overview of Experimental and Clinical Studies R. Alonso, F. Marín, M. González, P. Guelmes, C. Bellido, G. Hernández, R. Marín, M. Díaz, J.E. Sánchez-Criado Introduction Hypothalamus-Pituitary-Ovarian Axis of Mammals GeneralAspects FunctionalOrganization Estrogen Feedback Regulation ofhypothalamus-pituitaryaxis Overview of Hypothalamic-Pituitary Function attimeofgonadotropinsurge EffectsofSERMsonHypothalamus-Pituitary-OvarianAxis ExperimentalStudiesintheRat Lessons in SERM Behavior from Effects of Tamoxifen onratpituitaryfunction ClinicalStudies Summary and Conclusions References PureAntiestrogens Carlos Hermenegildo Introduction TypeI TypeII ChemicalStructureandClassification

9 X Contents 6.3 MechanismofAction EffectsofPureAntiestrogens InVitroStudies ExperimentsinAnimals ClinicalStudies ClinicalUtility References Part II Clinical Area 7 Physiological Regulation of Bone Metabolism and Estrogen Agonism Miguel Angel García-Pérez NormalBoneRemodeling ExecutiveCells:OsteoblastsandOsteoclasts Role of Proinflammatory Cytokines in Bone Resorption TheRANKL/RANK/OPGSystem Bone Remodeling After Estrogen Deficiency Effects of Estrogen and Agonist of Estrogen Receptor on Bone Cells Conclusions References The Role of SERMs in the Treatment of Osteoporosis Adolfo Díez-Pérez, José Luis Dueñas-Díez Introduction ExperimentalResults Tamoxifen Raloxifene OtherSERMs ClinicalEffectsofSERMs Tamoxifen Raloxifene BoneQualityandItsRelevance Future SERMs References Cardiovascular Disease and SERMs Antonio Cano TheFocalPhenotypeofCVD TheCrucialRoleoftheEndothelium EstrogenAgonismandCVD

10 Contents XI Lipids VascularWall SERMsasanAlternativetoEstrogensinCVD ActionsofSERMs ArterialDisease VTED ConclusionandOutlookfortheFuture References SERMs and the Breast Joaquim Calaf i Alsina, Antonio Cano Sanchez Introduction BiologyofBreastDevelopmentanditsEndocrineRegulation Framework of Breast Cancer Research Relationship Between Estrogens and Breast Cancer EndogenousEstrogens ExogenousEstrogens Pharmacological Blockade of Estrogen Receptors: TheConceptofChemoprophylaxis Tamoxifen as Adjuvant Therapy inearlyer(+)breastcancer Tamoxifen in Primary Prevention of ER(+) Breast Cancer DrawbacksofTamoxifenasaPreventiveAgent RaloxifeneandBreastCancer ClinicalStudies EstrogenReceptorStatus EstrogenCirculatingLevelsandRaloxifeneProtection BoneDensityandEffectofRaloxifeneontheBreast OtherConditionsRelatedtoRaloxifeneProtection RaloxifenasaBreastCancerPreventiveAgent NewPerspectives References Endometrial Effects of SERMs Santiago Palacios Introduction MechanismofActionintheEndometrium Tamoxifen Raloxifene TamoxifenandEndometrium:ClinicalConsideration UltrasonographicFindings

11 XII Contents HystologicalFindings TamoxifenandRiskofEndometrialCancer Raloxifene DataObtainedfromBiopsy UltrasonographicDataandSymptomatology Others SERMs Arzoxifene BazedoxifeneAcetate Lasofoxifene Ospemifene Conclusions References Benign Gynecological Diseases and SERMs Stefano Palomba, Fulvio Zullo Introduction UterineLeiomyomas TreatmentsofUterineLeiomyomas SERMsandUterineLeiomyomas Endometriosis TreatmentsofEndometriosis SERMsandEndometriosis Conclusions References Other Clinical Effects of SERMs P. Acién, F. Quereda, M.I. Acién UrogenitalTract VaginalTrophismandDyspareunia PelvicFloorFunctionandUrinaryDisorders Centralnervoussystem HotFlashesandBetaEndorphins Mood,Sleep,WakingEpisodes CognitiveFunction,Alzheimer sdisease(ad) Libido,SexualFunction GallbladderandHepatobiliarSystem DesmoidsandMesentericFibromatosis EndocrineFunctions InsulinSensitivityandDiabetes ThyroidFunction Eye, Cataracts

12 Contents XIII 13.7 OtherEffects Arthritis HemorheologicalEffects QualityofLife(QoL) References The Role of SERMs in the Management of Postmenopausal Women Joaquim Calaf i Alsina Introduction IdentifyingTroublesandThreats CardiovascularRisk MenopausalSyndrome Osteoporosis BreastCancer InterventionTools LifestyleOptimization HormoneTherapy CardioprotectiveTreatments BoneResorptionInhibitors BreastCancerRisk AdressingHealthExpectancyImprovement PolyApproachandMultitasking PharmacologicalPolyApproach MultitaskingDrugs DynamicDecision-MakingDiagram References Subject Index

13 List of Contributors M.I. Acién Service of Obstetrics and Gynecology San Juan University Hospital and Dept/Division of Gynecology Miguel Hernández University Campus of San Juan Alicante, Spain P. Acién Service of Obstetrics and Gynecology San Juan University Hospital and Dept/Division of Gynecology Miguel Hernández University Campus of San Juan Alicante, Spain Rafael Alonso Laboratorio de Neurobiología celular Departamento de Fisiología and Instituto de Tecnologías Biomédicas C. Bellido Department of Cell Biology Physiology and Immunology University of Córdoba Córdoba, Spain María Carmen Barbancho Department of Obstetrics and Gynecology Santa Cristina University Hospital Madrid, Spain Joaquim Calaf i Alsina Servei d Obstetricia i Ginecologia Hospital de la Santa Creu i Sant Pau C/ Sant Antoni M. Claret Barcelona Antonio Cano Sanchez Department of Pediatrics, Obstetrics and Gynecology University of Valencia Valencia, Spain Mario Díaz Laboratorio de Fisiología Animal Departamento de Biología Animal and Instituto de Tecnologías Biomédicas

14 XVI B. Nicolás Díaz Chico Canary Islands Cancer Research Institute Department of Biochemistry and Physiology Universidad de Las Palmas de Gran Canaria Juan C. Díaz Chico Canary Islands Cancer Research Institute Department of Biochemistry and Physiology Universidad de Las Palmas de Gran Canaria Adolfo Díez-Pérez Department of Internal Medicine and Infectious Diseases Hospital del Mar Autonomous University of Barcelona Unidad de Investigación en Fisiopatología Ósea y Articular (IMIM) Barcelona, Spain José Luis Dueñas-Díez University of Sevilla Head Department of Obstetrics and Gynaecology Hospital Universitario Virgen Macarena Sevilla, Spain Eduardo Escrich Escriche Multidisciplinary Group for the Study of Breast Cancer Department of Cellular Biology, Physiology and Immunology Universidad Autónoma de Barcelona List of Contributors Benito García Marrero Instituto de Productos Naturales yagrobiología CSIC Instituto de Tecnologías Biomédicas Miguel Angel García-Pérez Research Unit Hospital Clínico Universitario de Valencia and Department of Genetics Faculty of Biology Valencia, Spain Tomás Gomez Laboratorio de Fisiología Animal Departamento de Biología Animal Instituto de Tecnologías Biomédicas M. González Departments of Physiology and Animal Biology & Institute of Biomedical Technologies University of La Laguna La Laguna, Spain P. Guelmes Departments of Physiology and Animal Biology & Institute of Biomedical Technologies University of La Laguna La Laguna, Spain

15 List of Contributors Carlos Hermenegildo Research Unit Hospital Clínico Universitario of Valencia. Unidad Central de Investigación and Dentistry University of Valencia Avda. Blasco Ibañez, Valencia, Spain G. Hernández Departments of Physiology and Animal Biology & Institute of Biomedical Technologies University of La Laguna La Laguna, Spain Fernando Marín Eli Lilly and Company Lilly Research Center Windlesham, Surrey, UK Raquel Marín Laboratorio de Neurobiología celular Departamento de Fisiología Instituto de Tecnologías Biomédicas Jorge Marrero-Alonso Laboratorio de Fisiología Animal Departamento de Biología Animal Instituto de Tecnologías Biomédicas Domingo Navarro Bosch Canary Islands Cancer Research Institute Department of Biochemistry and Physiology Universidad de Las Palmas de Gran Canaria Santiago Palacios Institute Palacios of Woman s Health Calle Antonio Acuña, Madrid, Spain Stefano Palomba Department of Obstetrics & Gynecology University Magna Greacia of Catanzaro Italy F. Quereda Service of Obstetrics and Gynecology San Juan University Hospital and Dept/Division of Gynecology Miguel Hernández University Campus of San Juan Alicante, Spain J.E. Sánchez-Criado Department of Cell Biology, Physiology and Immunology University of Córdoba Córdoba, Spain Fulvio Zullo Department of Obstetrics & Gynecology University Magna Greacia of Catanzaro Italy XVII