`adedby:8,Kent-
`
`
`
`£06343lo1622221524-13133201?3:638:04PM
`
`Down
`
`InnoPharma Exhibit 1082.0001
`
`
`
`
`
`
`
`2QwouwwuwEommmxe.fimmfmmmwwe
`
`
`
`mgmow.memH3@manEBoo
`
`InnoPharma Exhibit 1082.0002
`
`
`
`Basil A. Stall, London (Editor)
`
`
`Endocfine
`Management
`of
`Cancer
`
`‘OOOQOOUQGOOOOOOGQOG‘OOOOOO.‘fiCOOO§OOOCOOfifitOOOOOCQ.
`
`
`
`
`
`7 figures and 10 tables, 1988
`
`@RlEEUE
`
`
`Basel ‘ Mfinchen - Paris - London - NewYork - NewDelhi - Singapore ~Tokyo - Sydney
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4804PM
`
`InnoPharma Exhibit 1082.0003
`
`
`
`
`
`Library of Congress Cataloging-in-Publication Data
`Endocrine management of cancer.
`Includes bibliographies and index.
`Contents: v. 1. Biological bases.
`1. Cancer — Chemotherapy.
`2. Hormone therapy.
`3. Hormones — Agonists — Therapeutic use.
`4. Hormones — Antagonists — Therapeutic use.
`I. Stoll, Basil A. (Basil Arnold)
`[DNLMz 1. Hormones — therapeutic use.
`RC271.H55E528
`1988
`616.99’4061
`ISBN 3—8055—4687—4 (set)
`ISBN 3—8055—4685—8 (v.1)
`ISBN 3—8055—4686—6 (v.2)
`
`2. Neoplasms — drug therapy. QZ 267 E56]
`87—29872
`
`Drug Dosage
`The authors and the publisher have exerted every effort to ensure that drug selection and
`dosage set forth in this text are in accord with current recommendations and practice at the
`time of publication. However, in view of ongoing research, changes in government regulations,
`and the constant flow of information relating to drug therapy and drug reactions, the reader is
`urged to check the package insert for each drug for any change in indications and dosage and
`for added warnings and precautions. This is particularly important when the recommended
`agent is a new and/or infrequently employed drug.
`
`All rights reserved.
`No part of this publication may be translated into other languages, reproduced or utilized in
`any form or by any means, electronic or mechanical, including photocopying, recording,
`microcopying, or by any information storage and retrieval system, without permission in
`writing from the publisher.
`
`©
`
`Copyright 1988 by S. Karger AG, PO. Box, CH— 4009 Basel (Switzerland)
`Printed in Switzerland by Friedrich Reinhardt AG, Basel
`ISBN 3—8055—4687—4 (set)
`ISBN 3—8055—4685—8 (v.1)
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4804PM
`
`InnoPharma Exhibit 1082.0004
`
`
`
`Contents
`
`Contributors
`Preface
`.
`.
`
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`Steroids, Mediators and Growth Factors
`
`Y.S. Cho—Chung
`
`1 Models of Tumor Regression in Endocrine-Related Cancer
`Regression due to Autophagic Cell Death (Apoptosis)
`.
`.
`.
`.
`.
`.
`.
`.
`Regression due to Cell Differentiation
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Regression due to Cell Differentiation and Apoptosis
`.
`.
`.
`.
`.
`.
`.
`.
`Conclusion .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`J.D. Simnett
`
`2 Hormonal Regulation ofProtein Synthesis and Cell Differentiation
`Genetic Control of Neoplasia
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Protein Synthesis and Growth Control
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Hormonal Regulation of Gene Expression .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Steroids and the Control of Morphogenesis
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Potential for the Hormonal Control of Neoplasia .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`MJ. Tisdale
`
`IX
`. ..
`.
`.
`. XI
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`1
`1
`4
`7
`9
`10
`
`14
`14
`l6
`17
`19
`21
`22
`
`3 Role of Intracellular Mediators in Hormonal Mechanisms .
`Cyclic Nucleotides .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Phosphoinositides
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Phorbol Esters
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Prostaglandins, Thromboxanes and Prostacyclin
`.
`,
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Conclusion .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`
`J.R. C. Sainsbury
`
`4 Growth Factors and Their Receptors as Mediators of Response .
`Presence of Growth Factors and Receptors in Human Tumours
`.
`.
`.
`.
`.
`.
`.
`Possible Strategies for Intervention in Growth Factor-Mediated Pathways .
`.
`
`Conclusion .
`References
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`26
`26
`30
`31
`31
`33
`33
`
`35
`36
`38
`
`41
`42
`
`g
`gg
`
`e s
`
`a E
`
`InnoPharma Exhibit 1082.0005
`
`
`
`Contents
`
`R.A. Hawkins, W.R. Miller
`
`5 Endogenous Sex Hormones in Cancer Development
`Breast Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Endometrial Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Prostatic Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Ovarian Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Testicular Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`Cancers of Non-Target Organs .
`Conclusion .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`Factors in Hormonal Responsiveness
`
`J. T. Hamm, J. C. Allegra
`
`6 Loss of Hormonal Responsiveness in Cancer .
`Selective Elimination of Hormone-Dependent Cells
`.
`Changes in Cellular Metabolism .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Changes in Hormonal Balance of the Host
`.
`.
`.
`.
`.
`.
`Conclusion .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`H. S. Poulsen
`
`VI
`
`45
`45
`48
`49
`50
`51
`
`52
`55
`55
`
`61
`61
`63
`68
`69
`69
`
`72
`72
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`7 In vitro Observations in Relation to Response .
`Methods in Use
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`Clonogenic Assay
`Human Breast Cancer Cell Lines
`Clinical Implications
`.
`.
`.
`.
`.
`.
`Conclusion .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`DE. Merkel, CK. Osborne
`
`8 Steroid Receptors in Relation to Response
`Mechanism of Steroid Hormone Action
`.
`.
`.
`.
`.
`Breast Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Endometrial Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Prostate Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`
`.
`.
`.
`.
`
`P. Davies
`
`9 Steroid Metabolism in Tumours in Relation to Response
`Steroid Metabolism in Prostate Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Steroid Metabolism in Breast Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Steroid Metabolism in Endometrial Cancer
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Conclusion .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`
`75
`77
`80
`80
`81
`
`34
`84
`85
`91
`94
`96
`
`. 100
`. 100
`. 103
`. 106
`. 108
`. 109
`
`
`
`Downloadedby:8,Kent-406343
`
`
`
`
`
`1622221524-15135201?K4804PM
`
`InnoPharma Exhibit 1082.0006
`
`
`
`Contents
`
`H.K. Adam
`
`Pharmacokinetics of Agents in Relation to Response
`Rationale of Metabolic Studies
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`Aminoglutethimide
`Medroxyprogesterone Acetate
`Tamoxifen
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Conclusion .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`.
`.
`
`J. T. Isaacs
`
`10
`
`11
`
`.
`.
`
`VII
`
`. 112
`. 112
`
`. 113
`. 116
`.
`118
`. 120
`.
`121
`
`. 125
`. 125
`. 127
`. 128
`. 129
`. 130
`. 132
`. 135
`. 136
`. 136
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`Clonal Heterogeneity in Relation to Response .
`.
`.
`Morphologic Heterogeneity .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Immunologic Heterogeneity
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Cell-Enzyme Studies .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`DNA Ploidy and Chromosomal Karyotype .
`.
`.
`.
`.
`.
`.
`.
`Steroid Receptor Heterogeneity and Hormonal Sensitivity .
`Mechanisms for Development of Clonal Heterogeneity .
`.
`.
`Therapeutic Implications
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`,
`Conclusion .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`Subject Index .
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`l4l
`
`
`
`Downloadedby:8,Kent-6106343
`
`
`
`
`
`1622221524-15135201??:48:04PM
`
`InnoPharma Exhibit 1082.0007
`
`
`
`Contents Vol. 2: Contemporary Therapy
`
`The Role of Current Agents
`
`MAUJNH
`
`A. U. Buzdar: Progestins in Cancer Treatment
`B.J.A. Furr, R.A. V. Milsted: LH-RH Analogues in Cancer Treatment
`A.S. Bhatnagar, C. Nadjafi, R. Steiner: Aromatase Inhibitors in Cancer Treatment
`U. W. Tunn, A. Radlmaier, E Neumann: Antiandrogens in Cancer Treatment
`V.C. Jordan: Antiestrogens in Cancer Treatment
`
`New Aspects of Therapy
`
`M.J. Dunne, K. Kutz: Somatostatin Analogues in Cancer Treatment
`B.A. Stoll: Combination Endocrine Therapy — Concurrent or Sequential?
`D. Rausch, D.T. Kiang: Interaction between Endocrine and Cytotoxic Therapy
`S. Kvinnsland, S. Gundersen: Prospects for Alternating Endocrine Therapy
`R.D. Gambrell, Jr.: Hormonal Medication and Mitogenic Dangers
`K. Vallis, J. Waxman: Tumour Flare in Hormonal Therapy
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4804PM
`
`InnoPharma Exhibit 1082.0008
`
`
`
`
`
`Contributors
`
`Adam, H.K., BSc, PhD, Pharmacokinetics Section, Safety of Medicines Department,
`ICI Pharmaceuticals Division, Macclesfield, UK
`Allegra, J.C., MD, Professor and Chairman, Department of Medicine, University of
`Louisville, Louisville, Ky., USA
`Cho-Chung, Y.S., MD, PhD, Chief, Cellular Biochemistry Section, Laboratory of
`Tumor Immunology and Biology, National Cancer Institute, Bethesda, Md., USA
`Davies, P., PhD, Tenovus Institute for Cancer Research, Welsh National School of
`Medicine, Cardiff, UK
`Hamm, J.T., MD, Division of Medical Oncology, University of Louisville School of
`Medicine, Louisville, Ky., USA
`Hawkins, R.A., PhD, Senior Lecturer, University Department of Clinical Surgery,
`The Royal Infirmary, Edinburgh, UK
`Isaacs, J .T., PhD, Associate Professor, The Oncology Center, Associate Professor,
`The Department of Urology, The Johns Hopkins University School of Medicine,
`Baltimore, Md., USA
`Merkel, DE, MD, Fellow in Medical Oncology, University of Texas Health Science
`Center at San Antonio, San Antonio, Tex., USA
`Miller, W.R., PhD, Reader, University Department of Clinical Surgery, The Royal
`Infirmary, Edinburgh, UK
`Osborne, C.K, MD, Professor of Medicine, University of Texas Health Science Center
`at San Antonio, San Antonio, Tex., USA
`Poulsen, H.S., MD, PhD, Specialist and Reader in Oncology and Head of Receptor
`Laboratory, University Radium Centre, Aarhus, Denmark
`Sainsbury, J.R.C., MD, MS, FRCS, Honorary Senior Registrar, CRC Clinical Research
`Fellow, University Department of Surgery, Royal Victoria Infirmary,
`Newcastle upon Tyne, UK
`Simnett, J.D., MA, BSc, PhD, Lecturer in Experimental Pathology, Department of
`Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
`Tisdale, M.J., BSc, PhD, DSc, Reader in Pharmaceutical Sciences, Aston University,
`Birmingham, UK
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4804PM
`
`InnoPharma Exhibit 1082.0009
`
`
`
`
`
`
`
`2QwouwwuwEommmxe.fimmfmmmwwe
`
`
`
`mgmow.memH3@manEBoo
`
`InnoPharma Exhibit 1082.0010
`
`
`
`Preface
`
`The last decade has seen almost incredible advances in our knowledge
`of the molecular biology of the cancer cell, and this has provided vital clues
`
`as to why tumours behave in a particular way in each individual patient.
`The new knowledge includes evidence on how growth factors which are
`essential to the growth of the cancer cell may be either switched on or off.
`In addition, we have developed insights into the production, metabolism
`and interaction of steroid and peptide hormones in malignant tissue, and
`
`why they may exert variable effects on the proliferative, invasive and
`differentiation activities of the cancer cell in endocrine target organs.
`
`The book is unique in that it attempts to formulate principles aiming to
`link endocrine therapy by similar agents in cancers of the breast, prostate
`and uterus. Progress in the field has been hindered in the past by poor
`communication between the different specialist departments — surgical,
`urological and gynaecological — responsible for clinical research into each of
`the cancers. The book also breaks fresh ground in that it reviews models of
`hormonally-induced regression of cancer and emphasises how they differ
`from the model of regression following cytotoxic therapy. Different models
`imply not only the need for different schedules of treatment to deal with
`autonomy, but also the need for different methods of assessing response
`which are likely to be reflected in more prolonged survival.
`The book aims to provide answers to questions which are rarely
`addressed in the literature. Does endocrine therapy lead to a state of
`dormancy in tumour growth? Do different endocrine modalities act through
`different mechanisms in causing regression of tumour growth, and how does
`the mechanism differ from that of cytotoxic therapy? How far do observa-
`tions on animal tumours or tissue culture studies provide information which
`
`can be extrapolated to the clinical situation? How does the tumour metab-
`olism of hormones affect response to hormonal manipulation? Are steroid
`
`receptors markers of tumour responsiveness or are they actively involved in
`tumour regression? What is the mechanism of subsequent tumour reacti-
`vation and its occasional response to secondary endocrine therapy?
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4804PM
`
`InnoPharma Exhibit 1082.0011
`
`
`
`Preface
`
`XII
`
`It has become increasingly difficult for the busy clinician to keep
`
`abreast of new advances which provide pointers to future cancer manage-
`ment. This book is intended to expand the perspectives of the large numbers
`
`of clinicians practising endocrine therapy as part ofthe overall management
`of patients with cancers of the breast, prostate or uterus.
`
`London, 1988
`
`Basil A. Sloll
`Consulting Physician,
`Oncology Department,
`St.Thomas’ Hospital,
`London
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4804PM
`
`InnoPharma Exhibit 1082.0012
`
`
`
`10 Pharmacokinetics of Agents
`in Relation to Response
`H.K. Adam
`
`This chapter examines pharmacokinetic data on some endocrine
`
`agents presently in use in the clinic (aminoglutethimide, medroxyprogeste-
`rone and tamoxifen) both to assist in their use and also to identify areas
`where problems might occur. Disease states can result in malabsorption of
`
`oral agents, affect the ability of plasma proteins to bind drugs and may be
`associated with impairment of kidney and liver function. All these changes
`can alter the effectiveness of a drug, especially the last, which represents the
`main routes of elimination of foreign substances.
`
`Rationale of Metabolic Studies
`
`The success of a drug therapy represents a victory by the clinical
`
`pharmacologist over the elimination mechanisms of the host. The goal of
`the former is to achieve sufficiently high concentrations of the therapeutic
`agent at the site ofaction, while the host is continually trying to eliminate the
`foreign substance. It must be borne in mind that most drugs are new
`chemical substances that the host has not met before. Thus, although he has
`
`a variety of different metabolic pathways and excretory mechanisms avail-
`able, these must be adapted from existing mechanisms which have been
`evolved to deal with endogenous or completely different exogenous sub-
`stances.
`
`The basic principle behind most of these pathways is for the body to
`attempt to make the compound more water soluble by chemical modifica-
`tion of the administered drug (phase I metabolism), and/or to attach a
`water-soluble grouping such as sulphate or glucuronide (phase II metabo-
`lism). Susequent elimination is then through the kidney or bile. Because
`these changes are adapted from natural pathways, the host sometimes ‘gets it
`
`wrong’ by converting the parent drug into a substance with is more difficult
`to eliminate than the parent drug. This may have a significant effect on the
`overall activity of the drug if the metabolite also possesses pharmacological
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4308PM
`
`InnoPharma Exhibit 1082.0013
`
`
`
`10
`
`Pharmacokinetics of Agents in Relation to Response
`
`113
`
`activity. Equally, it can be used to advantage by using the metabolic capacity
`of the host to convert an inactive compound (pro-drug) to an active spe-
`cies.
`
`The clinical pharmacologist can modify the frequency at which he
`
`administers the drug, he can modify the route by which he gives it and once
`he understands how the body’s defence mechanisms eliminate a given drug,
`
`he can modify its chemical structure to devise new compounds of equal or
`greater potency which are specifically designed to counteract these excretory
`mechanisms.
`
`It is necessary to identify factors which could affect the drug concen-
`trations in the body because a drug must reach its site of action before it can
`elicit its effect. But what is often impossible to assess, is the quantitative
`
`relationship between the amount of drug in the body and the extent and
`duration of the therapeutic effect. The situation is further complicated by
`the fact that in most cases, sequential drug measurements are usually
`restricted to body fluids such as blood or urine, which are distant, both
`physically and conceptually, from the site of action. Thus, whereas host
`metabolism (i.e. the effect the host has on the drug) is frequently well
`understood, the relationship between this and response (i.e. the effect the
`drug has on the host) is considerably more difficult to quantitate.
`Before the pharmacokinetics and metabolism of an agent can be inves-
`tigated, the two primary requirements are an assay procedure for the drug
`and a radiolabelled form of the agent. To produce valid information the
`former should be sensitive enough to detect the drug at therapeutic doses
`and, equally important, be specific for the drug in question. The metabolism
`of foreign substances is studied by the administration of the drug labelled
`with a suitable radiotracer. As long as this tracer is biologically stable, the
`administered dose can be followed by examining the excreted material not
`only for quantity (routes of excretion) but also to allow the major metabo-
`lites to be identified.
`
`Aminoglutethimide (AG)
`
`Metabolism ofAG
`The structure of AG (1) and its presently known metabolites are shown
`
`in figure 1. N-acetyl AG (11) was initially identified in the urine of healthy
`
`volunteers who had received a single oral dose of Ag [1]. Further investi-
`gations in volunteers’ urine revealed the presence of N-formyl Ag (III) and
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4308PM
`
`InnoPharma Exhibit 1082.0014
`
`
`
`
`
`
`
`1622221524-15135201??:4?:08PM
`
`
`
`Downloadedby:8,Kent-406343
`
`Adam
`
`1 14
`
`NHZ
`
`02H
`
`o
`
`I
`
`NH
`
`0
`
`N”°°c“3
`
`NHCHO
`
`N02
`
`0
`
`N
`H
`
`N
`H
`
`o
`
`o
`II
`
`c H
`
`o
`I
`
`NHOH
`
`o
`
`N
`H
`
`N
`H
`
`o
`
`o
`
`111
`
`c H
`
`o
`E
`
`NH2
`
`N
`H
`
`o
`
`N
`H
`
`o
`
`0
`N
`
`c H
`
`o
`El
`
`NHCOCH3
`
`fiH3
`HOCH
`
`NHz
`
`Crz—CONHZ
`CH2
`
`0
`
`u
`
`o
`m
`
`0
`
`o
`IX
`
`Fig. l. Aminoglutethimide (I) and its human metabolites.
`
`nitroglutethimide (IV) [2]. In 1984, Jarman et al. [3] identified hyroxylam-
`inoglutethimide (V) from the urine of patients during chronic AG therapy.
`Finally, the same group identified a further four urinary metabolites (VI),
`(VII), (VIII) and (IX) from patients’ urine [4].
`
`Quantification of the urinary metabolites has been attempted by sev-
`eral groups [1, 2, 5—8], and differences in their findings can probably be
`explained by a combination of factors. First, different analytical procedures
`
`were used. Second, it has been shown that AG is subject to genetic poly-
`morphism, and the acetylator status of subjects, whether it be characterised
`by sulphadimidine [5] or dapsone [8], has a significant effect on the rate of
`metabolism. Third, and probably most important, it has been shown that
`
`AG induces its own metabolism [9], so that the metabolic pattern is likely to
`change between acute and chronic dosing. Testing of the metabolites has
`
`shown that they are considerably less active than the parent drug [4] and
`
`InnoPharma Exhibit 1082.0015
`
`
`
`10
`
`Pharmacokinetics of Agents in Relation to Response
`
`115
`
`thus it seems probable that the therapeutic affect of AG resides almost
`completely in the unchanged drug.
`In addition to inducing its own metabolism (autoinduction) it has been
`shown that AG can affect the disposition of other drugs. Co-administration
`with warfarin for 14 days caused a dose-related increase in clearance of this
`latter drug, with increases of up to a mean of 107% at high dose (1,000
`
`mg/day) AG therapy [10]. Similar effects have been seen on dexamethasone
`[11], theophylline and digitoxin [12].
`
`Pharmacokinetics ofAG
`There are no reports comparing an oral dose of AG with an intravenous
`dose to assess absolute bioavailability, but two sets of data indicate that
`
`absorption of an oral dose is good. Recovery of 14C in the urine of subjects
`given an oral I4C dose of AG averaged about 90% [13], and Thompson et al.
`[7] showed that there was no difference in the pharmacokinetic profile
`between solution and tablet formulations.
`
`It has recently been suggested [13] that a change in the volume of
`distribution may be of more importance than autoinduction in affecting the
`clearance of the drug. But in the light of its significant effect on other drugs
`as mentioned above, it would still appear that induction of hepatic enzymes
`has a major influence on AG diSposition. It has recently been claimed that
`steady state serum concentrations are linearly related to AG dose over the
`range 125— 1,000 mg/day [14]. However, this study averaged concentrations
`taken anything between 10 and 360 min after the dose in different patients
`and, although encouraging, should be treated with caution.
`
`Implications for Therapeutic Use
`Given the low degree of protein binding, it is unlikely that drug-drug
`interactions could arise from this direction. However, the evidence that AG
`
`can influence the disposition of several other drugs as a result of its
`induction of hepatic drug-metabolising enzymes, should lead to caution
`when it is used in combination with other agents, especially those with
`narrow therapeutic ranges. AG has a relatively short half-life and thus no
`accumulation occurs on repeated administration. Hence multiple daily
`
`therapy seems necessary and compliance/malabsorption problems could
`lead to loss of efficacy.
`It has been suggested that the CNS side effects of AG are dose related,
`and that these are transient because of the autoinduction, resulting in lower
`
`drug concentrations [9]. Equally, it has been suggested that an incremental
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4308PM
`
`InnoPharma Exhibit 1082.0016
`
`
`
`Adam
`
`1 16
`
`dose regimen will provide a better change of reducing side effects. However,
`there is no clear evidence ofwhat constitutes a ‘therapeutically effective’ or a
`‘toxic concentration’ of AG. Thus, a balance between a low dose, with its
`
`likely lower incidence of Side effects, and a higher dose, with possible
`increased change of therapeutic benefit (in parallel with clinical observa-
`tions) seems the optimal mode of administration of this drug.
`
`Medroxyprogesterone Acetate (MPA)
`
`Metabolism ofMPA
`Although MPA has been in clinical use for some 30 years, its metabo-
`lism in man has not been fully elucidated. Administration of 14C-MPA
`
`(labelled at C-6), intravenously, to 6 subjects led to recovery of a mean of
`33% of the dose in the urine in 4 days [15]. In a more recent study in two
`
`subjects, an average of 35% of the dose was recovered in the urine in 9 days
`[16]. After administration by the intramuscular route, urinary recoveries
`were found to vary between studies: the first study reported only about 10%
`recovery after 6 days [17] but in a more recent study 47% of the dose was
`found in the urine after 14 days [1 8]. This discrepancy probably results from
`different release rates from the intramuscular depot.
`
`After oral administration of 100 mg 3H-MPA, urinary recoveries were
`variable, ranging from 16 to 38% in 6 days [17] in one study, and 30% in 2
`days another [16]. However, in contrast to the i.m. route, the absorption by
`the oral route appeared to be rapid, and the bulk of the radioactivity was
`recovered in the first 24 h after dosing. Faecal recovery did not account for
`the residue of the dose. Thus, total recovery of a radiolabelled dose of MPA
`has not been achieved.
`
`Investigations on the metabolites of MFA in humans have resulted in
`the identification of the compounds shown in figure 2. They probably
`
`appear in urine as glucuronide conjugates, since treatment with B-glucuron-
`idase is necessary to release them in the free form. It has been suggested [16]
`that the 21-hydroxy compound (11), as isolated and identified by Helmreich
`
`and Huseby [19], is the true metabolite and that the 21-acetoxy isomer [20]
`is an artefact of cross-esterification during deconjugation. The trihydroxy
`compound (III) has also been isolated [16] but it is uncertain whether this
`was a true metabolite or an artefact. It has also been demonstrated that
`
`reduction in the A ring can occur to yield the 3a-hydroxy compound (IV).
`The metabolism of MPA is thus poorly understood.
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4308PM
`
`InnoPharma Exhibit 10820017
`
`
`
`
`
`
`
`1622221524-15135201?K4308PM
`
`
`
`Downloadedby:8,Kent-6306343
`
`10
`
`Pharmacokinetics of Agents in Relation to Response
`
`117
`
`i“C = 0
`--OAc
`
`lC
`
`I
`
`H3
`
`(Iznz—on
`c = 0
`--OH
`
`CH3
`C = O
`-0Ac
`
`: OH
`CH3
`]]I
`
`H0
`
`:
`CH3
`N
`
`(|:Hz—0H
`C = O
`"GAG
`
`o
`
`0
`
`o
`
`: 0H
`CH3
`II
`
`Fig. 2. Medroxyprogesterone acetate (1) and its human metabolites.
`
`Pharmacokinetics of MPA
`
`Data on the pharmacokinetics of MPA have been generated by a variety
`of assay procedures and after administration by several different routes
`
`[21—35]. For the high doses used in cancer treatment (SOD—1,500 mg/day), it
`has been shown that accumulation occurs on chronic administration but
`
`that interindividual variation in plasma levels is very large [32, 33]. This is
`true whether the dose is administered orally or intramuscularly, although in
`the later case plasma concentrations may be higher [28, 33—35]. This latter
`effect may be due to the continued release of drug from the i.m. depot, which
`has been shown in contraceptive studies to proceed for periods in excess of
`24 weeks. It has been suggested that a higher initial loading dose would be of
`
`value to more rapidly achieve a steady state [12], and a reducing dose
`regimen has also been reported to be acceptable after an initial 1,500 mg
`daily oral treatment [21].
`
`Implications for Therapeutic Use
`It is only relatively recently that the pharmacokinetics of MPA at the
`
`high doses used in cancer therapy have been investigated. Despite the
`
`problems associated with the variations of assay procedures, it is generally
`agreed that about a month’s dosing is required before steady state conditions
`are achieved after both oral and intramuscular administration.
`
`There is some disagreement in the literature, but the balance of evi-
`
`dence suggests that the effective bioavailability of unchanged drug is higher
`
`InnoPharma Exhibit 1082.0018
`
`
`
`Adam
`
`1 18
`
`after intramuscular administration, although tissue retention is extensive.
`
`Although the average pattern of drug concentrations during therapy by
`either route fits with pharmacokinetic theory [36], there is very wide
`intersubject variability in steady state levels [25, 32, 34]. It has been
`suggested that, because of the different pharmacological effects of high and
`low dose MPA (and by implication high and low drug serum levels),
`individual dosing based on pharmacokinetic monitoring would be helpful
`[30].
`
`Tamoxifen
`
`Metabolism of Tamoxifen
`
`The metabolites of tamoxifen identified in man are illustrated in fig-
`ure 3. It is clear that the metabolism of tamoxifen is complex, and results in
`
`numerous products. It is possible that the hydroxylated metabolites iden-
`
`tified in animals may also be found in man as polar conjugates. The degree
`to which these compounds may affect, and/or support, the therapeutic
`action of the parent drug is also complex. Metabolites, B, X, Y and Z have
`
`been shown to be antioestrogenic whereas metabolite B is oestrogenic [37,
`38] and the relative amounts of these compounds in the systemic circulation
`may not reflect the concentrations at the site of action. It is also possible that
`the metabolites in humans play a supportive role to the drug’s therapeutic
`effect.
`
`Pharmacokinetics of Tamoxifen
`No intravenous dosage form of tamoxifen is available and thus no
`
`comparison of oral and intravenous administration has been possible. After
`administration of a single oral dose of l4C—tamoxifen, collection of excreta
`for l 3 days rec0vered 14% of the dose in the urine and 51% in the faeces. The
`incomplete rec0very almost certainly occurred because collections were not
`
`continued for a sufficiently long period of time. This was confirmed by the
`presence of drug-related material in the blood at 14 days [39]. This finding is
`consistent with subsequent measurements of the half-lives of elimination of
`
`parent drug and metabolites, which have been reported as 7 days for
`tamoxifen and 14 days for N-desmethyltamoxifen. The absorption of
`tamoxifen is probably good, as the pharmacokinetic profiles after admin-
`
`istration of the drug in solution and in tablet form are indistinguishable
`[40].
`
`
`
`Downloadedby:8,Kent-6306343
`
`
`
`
`
`1622221524-15135201?K4308PM
`
`InnoPharma Exhibit 1082.0019
`
`
`
`10
`
`Pharmacokinetics of Agents in Relation to Response
`
`119
`
`
`
`CH3\
`
`HOCHZCHZO
`
`I
`
`I
`
`H\
`
`H/NCHZCHZO
`
`l
`
`I
`
`Metabolite X
`
`Metabolite Y
`
`Metabolite 2
`
`CH3\
`/NCH2CH20
`CH3
`
`
`
`H0
`
`00
`c2H5
`
`O
`
`CH3\
`/NCHZCH20
`
`OD
`C2H5
`
`"0 O
`
`Metabolite B
`
`Metabolite E
`
`3, 4 Dihydroxy tamoxifen
`
`Fig. 3. Tamoxifen (I) and its human metabolites.
`
`Published data on the serum concentrations of tamoxifen after single
`doses or chronic administration show good agreement, despite the use of a
`
`variety of different analytical procedures [37, 40—52]. Concentrations of
`both parent drug and its N—desmethyl metabolite (as a result of their long
`half-lives) are considerably higher during chronic administration than after
`a single dose, and there is general agreement that concentrations of the
`components in serum are in decreasing order of importance: metabolite X,
`tamoxifen, and metabolites Y and Z. Metabolites B, E and 3,4 dihydroxy
`tamoxifen, though present, are less than 1% of the parent drug concentra-
`tions.
`
`Given this complexity of circulating components, it is perhaps not
`surprising that no clear correlation between serum concentrations of drug or
`metabolites and clinical efficacy has been established. It has been reported
`by several groups that no clear differences could be established between
`
`responders and non-responders [44, 47, 48, 50, 51] even when tumour tissue
`was examined [44].
`
`
`
`Downloadedby:8,Kent-406343
`
`
`
`
`
`1622221524-15135201?K4308PM
`
`InnoPharma Exhibit 1082.0020
`
`
`
`Adam
`
`120
`
`Implications for Therapeutic Use
`Tamoxifen has a long elimination ha