Table Of Content3. 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
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©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].
