Drugs Affecting Growth of Tumours PDF
Preview Drugs Affecting Growth of Tumours
3. Umbruch9.4.2006 Milestones in Drug Therapy MDT Series Editors Prof. Michael J. Parnham, PhD Prof. Dr. J. Bruinvels Senior Scientific Advisor Sweelincklaan 75 PLIVA Research Institute Ltd NL-3723 JC Bilthoven Prilaz baruna Filipovic´a 29 The Netherlands HR-10000 Zagreb Croatia Drugs Affecting Growth of Tumours Edited by H.M. Pinedo and C.H. Smorenburg Birkhäuser Verlag Basel · Boston · Berlin Editors Herbert M. Pinedo Carolien H. Smorenburg Department of Medical Oncology VU Medical Center De Bolelaan 1117 1081 HV Amsterdam The Netherlands Advisory Board J.C. Buckingham (Imperial College School of Medicine,London,UK) R.J.Flower (The William Harvey Research Institute,London,UK) G. Lambrecht (J.W. Goethe Universität,Frankfurt,Germany) P.Skolnick (DOV Pharmaceuticals Inc.,Hackensack,NJ,USA) Library of Congress Cataloging-in-Publication Data Drugs affecting growth of tumours / edited by H.M. Pinedo and C. Smorenburg. p. cm. -- (Milestones in drug therapy) Includes bibliographical references. ISBN-13:978-3-7643-2196-3 (alk. paper) ISBN-10:3-7643-2196-2 (alk. paper) 1. Antineoplastic agents. I. Pinedo,H. M. II. Smorenburg,C. (Carolien),1965- III. Series. RS431.A64D785 2006 616.99'4061--dc22 2006045977 Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed biblio- graphic data is available in the internet at http://dnb.ddb.de ISBN 3-7643-2196-2 Birkhäuser Verlag,Basel - Boston - Berlin The publisher and editor can give no guarantee for the information on drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case. The use of registered names,trademarks etc.in this publication,even if not identified as such,does not imply that they are exempt from the relevant protective laws and regulations or free for general use. This work is subject to copyright. All rights are reserved,whether the whole or part of the material is concerned,specifically the rights of translation,reprinting,re-use of illustrations,recitation,broad- casting,reproduction on microfilms or in other ways,and storage in data banks. For any kind of use, permission of the copyright owner must be obtained. ©2006 Birkhäuser Verlag,P.O. Box 133,CH-4010 Basel,Switzerland Part of Springer Science+Business Media Printed on acid-free paper produced from chlorine-free pulp. TFC ∞ Cover illustration:Anthracycline-induced apoptosis pathway. See p. 29. With the friendly permission of K. Mross Printed in Germany ISBN-10:3-7643-2196-2 e-ISBN-10:3-7643-7407-1 ISBN-13:978-3-7643-2196-3 e-ISBN-13:978-3-7643-7407-5 987654321 www. birkhauser.ch V Contents List of contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX Kenneth W. Wyman,Igor Puzanov and Kenneth R. Hande Antimetabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Klaus Mross,Ulrich Massing and Felix Kratz DNA-intercalators – the anthracyclines . . . . . . . . . . . . . . . . . . . . . . . . . 19 Hans Gelderblom and Alex Sparreboom Topoisomerase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Manon T. Huizing Tubulin interacting agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 Alfonsus J.M. van den Eertwegh Vaccination therapies in solid tumors .......................... 133 Carolien H. Smorenburg and Alex Sparreboom Oral anticancer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 BartC. Kuenen Anti-angiogenesis agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 FerryA.L.M Eskens Signal transduction inhibitors ................................ 185 Rosalba Torrisi,Alessandra Balduzzi and Aron Goldhirsch Endocrine therapy of breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 VII List of contributors Alessandra Balduzzi, Research Unit of Medical Senology, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milano,Italy Ferry A.L.M. Eskens, Erasmus University Medical Center Rotterdam, Department of Medical Oncology,PO Box 2040,3000 CA Rotterdam,The Netherlands; e-mail:[email protected] Hans Gelderblom, Leiden University Medical Center, Department of Clinical Oncology, Albinusdreef 2, 2300RC Leiden, The Netherlands; e-mail: [email protected] Aron Goldhirsch, Department of Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy; and Oncology Institute of Southern Switzerland,Bellinzona & Lugano,Switzerland Kenneth R. Hande, Vanderbilt/Ingram, Cancer Center, 777 Preston Research Building,Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6307,USA; e-mail:[email protected] Manon T. Huizing, Antwerp University Hospital, Department of Oncology, Wilrijkstraat 10,2650 Edegem,Belgium; e-mail:[email protected] Felix Kratz,Tumor Biology Center at the Albert-Ludwig University Freiburg, Breisacher Strasse 117,79106 Freiburg i.Br.,Germany Bart C. Kuenen, Dpt. Medical Oncology, De Boelelaan 1117, 1081 HV Amsterdam,The Netherlands; e-mail:[email protected] Ulrich Massing, Tumor Biology Center at the Albert-Ludwig University Freiburg,Breisacher Strasse 117,79106 Freiburg i.Br.,Germany Klaus Mross, Tumor Biology Center at the Albert-Ludwig University Freiburg, Breisacher Strasse 117, 79106 Freiburg i.Br., Germany; e-mail: [email protected] Igor Puzanov, Vanderbilt/Ingram, Cancer Center, 777 Preston Research Building,Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6307,USA Carolien H. Smorenburg,Division of Immunotherapy,Department of Medical Oncology, Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam,The Netherlands; e-mail:[email protected] Alex Sparreboom, Clinical Pharmacology Research Core, Medical Oncology Clinical Research Unit, National Cancer Institute, 9000 Rockville Pike, Bldg. 10/Room 5A01, Bethesda, MD 20892, USA; e-mail: [email protected] Rosalba Torrisi, Research Unit of Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy; e-mail: [email protected] VIII List of contributors Alfonsus J.M. van den Eertwegh,Division of Immunotherapy,Department of Medical Oncology,Vrije Universiteit Medical Center, PO Box 7057, 1007 MB Amsterdam,The Netherlands; e-mail:[email protected] Kenneth W. Wyman,Vanderbilt/Ingram,Cancer Center,777 Preston Research Building,Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6307,USA IX Preface This volume of the series ‘Milestones’presents pharmacological, preclinical and clinical data of a wide range of anticancer agents varying from traditional cytotoxic agents to novel targeted small molecules. The chapters have been written by experienced pharmacologists and medical oncologists. This volume emphasizes the multidisciplinary approach and the need for a close collaboration between laboratory and clinic in the development of new anticancer therapies. In recent years,this type of research has resulted in many new anticancer drugs, of which some already are accepted as new standard therapies. The increasing knowledge of molecular biology has resulted in the development of a large number of agents specifically targeting cellular processes of tumor cells. Other strategies have focused on improving tradi- tional chemotherapeutic agents, better tolerability and improved patient com- pliance.Inthe field of immunology,advances have been made with novel vac- cination techniques, while research on endocrine treatments has been revived due to successful newtherapies for breast cancer. We are grateful to Hans-Detlef Klüber and Karin Neidhart for their sup- port in producing this edition. We would like to thank our colleagues for their critical reviewand comments. In the rapidly changing field of oncology,research remains endless. We are only at the beginning of a very exciting period of drug development. Carolien H. Smorenburg Herbert M. Pinedo Amsterdam,April 2006 Drugs Affecting Growth of Tumours 1 Edited by Herbert M. Pinedo and Carolien H. Smorenburg ©2006 Birkhäuser Verlag/Switzerland Antimetabolites Kenneth W. Wyman,Igor Puzanov and Kenneth R. Hande Vanderbilt/Ingram Cancer Center,777 Preston Research Building,Vanderbilt University School of Medicine,Nashville,Tennessee 37232-6307,USA Methotrexate and other folic acid antagonists Mechanism of action The synthesis of DNA requires reduced folates. Purine synthesis requires 10- formyltetrahydrofolate (CHO-FH ) as a methyl donor and 5,10-methylenete- 4 trahydrofolate (CH -FH ) as carbon donor in the synthesis of thymidine 2 4 (Fig.1). Methotrexate inhibits dihydrofolate reductase (DHFR) depleting cells of reduced folates, including CHO-FH and CH -FH [1]. Reduced folate 4 2 4 depletion does not account for all inhibition of DNA synthesis seen with methotrexate. Methotrexate is metabolized to methotrexate polyglutamates that contribute to cytotoxicity by directly inhibiting the folate dependent enzymes of thymidylate and purine biosynthesis (TS, AICAR, GAR; see Figure1. Mechanism of action of methotrexate. Reduced folates (FH,FH,CH-FH,CH-FH)are 2 4 2 4 0 4 needed for DNA synthesis. Methotrexate or methotrexate polyglutamates inhibit several enzymes (DHFR,TS,AICAR,GAR) critical in folate metabolism. 2 K.W. Wyman et al. Fig.1) [2,3]. Pemetrexed (Alimta®),a recently Food and Drug Administration (FDA) approved antifolate analog,is metabolized,like methotrexate,to polyg- lutamate forms within the cell [4]. Pemetrexed polyglutamate metabolites are also inhibitors of folate-dependent enzyme reactions. Cellular pharmacology Folates (and methotrexate) are transported into cells by two carrier systems:1) ahigh-capacity,low-affinity reduced folate carrier (RFC) and 2) a low-capaci- ty, high-affinity folate receptor system [5]. The RFC system appears to be the more clinically relevant methotrexate transporter. Cells with defective methotrexate transport are resistant to methotrexate [6]. Pemetrexed and raltitrexed (Tomudex®) can be transported by either system and may be less susceptible to drug resistance. Within the cell, methotrexate is converted to a polyglutamate form. Within 12–24h,most intracellular methotrexate exists as polyglutamates. Polyglutamates enter and exit cells only sparingly. The selec- tive cytotoxicity of methotrexate may come from increased formation of polyg- lutamates in neoplastic cells compared to normal tissues. The ability to gener- ate methotrexate polyglutamates correlates with methotrexate response [7]. Methotrexate and methotrexate polyglutamates are both potent tight-bind- ing inhibitorsof dihydrofolate reductase. An excess of drug is needed to main- tain total inhibition of DHFR [8]. Resistance to methotrexate can occur through increased expression of DHFR,development of a mutant DHFR with reduced affinity for methotrexate and amplification of the DHFR gene [9]. Moreover,decreased activity of folyl polyglutamate synthetase (FPGS),the enzyme which catalyzes polyglutamation,has been described as a mechanism of resistance to methotrexate [10, 11]. Increased activity of folyl polygluta- mate hydrolase (FPGH),the enzyme which catalyzes the reduction of number of glutamates, has been suggested as a mechanism of resistance to this drug [12]. For this reason ZD9331 has been developed, a quinazoline TS inhibitor that does not require polyglutamation in order to be active. In Phase I and II studies this drug seems promising. Another, recently discovered, mechanism of resistance to methotrexate, at least in vitro, is overexpression of the multidrug resistance proteins 1 and 2 (mrpl and mrp2) [13]. Leucovorin (a reduced folate) can be given to rescue cells from methotrex- ate. Leucovorin repletes reduced folate pools and competes with polygluta- mate inhibition of TS,GAR,and AICAR. The concentration of methotrexate within the cell and the duration of cell exposureto methotrexate are critical determinants of cytotoxicity. Cytotoxicity is directly related to time of drug exposure, but doubles only with a log increase in drug concentration. The concentration of reduced folate in the cir- culation affects cytotoxicity. Higher doses of leucovorin are needed to rescue cells exposed to higher methotrexate concentrations [14].
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