Deoxynucleoside Analogs In Cancer Therapy

482 Pages·2007·3.77 MB·English

by  Marçal Pastor-Anglada MSc

D A C T
EOXYNUCLEOSIDE NALOGS IN ANCER HERAPY
C D D
ANCER RUG ISCOVERY
D
AND EVELOPMENT
Beverly A. Teicher, Series Editor
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Schlag and Ulrike Stein, 2007 ogy:Basic Science and Clinical Thera-
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G. Swisher, 2007 Lieschke, 2004
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D
EOXYNUCLEOSIDE
A
NALOGS
C T
IN ANCER HERAPY
Edited by
G J. P ,
ODEFRIDUS ETERS PhD
Professor of Medical Oncology, VU University Medical Center
Amsterdam, The Netherlands
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Library of Congress Cataloging-in-Publication Data
Deoxynucleoside analogs in cancer therapy / edited by Godefridus J. Peters.
p. ; cm. -- (Cancer drug discovery and development)
Includes bibliographical references and index.
ISBN 1-58829-327-0 (alk. paper)
1. Deoxyribonucleotides--Therapeutic use. 2. Antineoplastic agents.
3. Cancer--Chemotherapy. I. Peters, Godefridus Johannes, 1952- . II. Series.
[DNLM: 1. Deoxyribonucleotides--therapeutic use. 2. Antineoplastic Agents--therapeutic
use. 3. Neoplasms--drug therapy. QV 185 D418 2006]
RC271.C5D45 2006
616.99'4061--dc22
2005036304
P
REFACE
Successful cancer chemotherapy relies heavily on the application of various
deoxynucleoside analogs. Since the very beginning of modern cancer chemotherapy,
a number of antimetabolites have been introduced into the clinic and subsequently
applied widely for the treatment of many malignancies, both solid tumors and
hematological disorders. In the latter diseases, cytarabine has been the mainstay of
treatment of acute myeloid leukemia. Although many novel compounds were
synthesized in the 1980s and 1990s, no real improvement was made. However, novel
technology is now capable of elucidating the molecular basis of several inborn errors
as well as some specific malignancies. This has enabled the synthesis of several
deoxynucleoside analogs that could be applied for specific malignancies, such as
pentostatin and subsequently chlorodeoxyadenosine (cladribine) for the treatment
of hairy cell leukemia. Already in the early stage of deoxynucleoside analog
development, it was recognized that several of these compounds were very effective
in the treatment of various viral infections, such as for the treatment of herpes
infections. This formed the basis initially for the design of azidothymidine and
subsequently many other analogs, which are currently successfully used for the
treatment of HIV infections. As a spin-off of these research lines, some compounds
not eligible for development as antiviral agents appeared to be very potent anticancer
agents. The classical example is gemcitabine, now one of the most widely applied
deoxynucleoside analogs, used for the (combination) treatment of non-small cell
lung cancer, pancreatic cancer, bladder cancer, and ovarian cancer. The knowledge
gained with the development of all of these compounds formed the basis for the
design of a number of novel analogs currently being used for the treatment of various
malignancies or currently in an advanced stage of development. Interestingly, several
of the nucleoside analogs are also targeted directly against cell cycle regulatory
proteins as well as other protein kinases.
In this volume of the Cancer Drug Discovery and Development series, the current
status of development and application of deoxynucleoside analogs has been
summarized. A number of scientists well known in their specific area contributed
with authoritative up-to-date reviews of their field. Their contributions were not
limited to writing, but also included sound advice on structure and topics that was
extremely valuable. Deoxynucleoside Analogs in Cancer Therapy is organized into
several parts: the first part (Chapters 1–5) deals with general aspects of drug uptake
and metabolism, the second deals with a number of specific drugs (Chapters 6–12),
v
vi Preface
while the last part covers pharmacokinetics, prodrugs, and specific applications such
as radiosensitization and the use of deoxynucleoside analogs as tracers.
In order to be taken up by the cell, deoxynucleoside analogs require specific
transporters, whereas other transporters can mediate efflux of (monophosphoryl-
ated) nucleosides. Novel technology enabled a rapid expansion of this field in the last
decade (Chapters 1–5). Subsequent phosphorylation of nucleoside analogs is
essential for their action and is mediated by a number of specific and less-specific
deoxynucleoside kinases; their characteristics and regulation are summarized in
Chapters 2 and 3. The role of nucleotidases in resistance to nucleoside analogs is
described in Chapter 4. Specific viral deoxynucleoside kinases were recognized to
be very suitable for local activation of otherwise inactive deoxynucleoside analogs.
The HSV-specific thymidine kinase was therefore extensively used in early gene
therapy studies. More active deoxynucleoside kinases with broad substrate specificity
seem very suitable for future gene therapy applications, as described in Chapters 3
and 16.
A chapter on cytarabine—the first real deoxynucleoside analog widely used in the
clinic—is essential to a complete book (Chapter 6). Various novel deoxynucleoside
analogs have been developed in the last decade; several aspects of their mechanism
of action and applications have been described throughout the above-mentioned
chapters, while several of these analogs are described extensively in specific chapters
on gemcitabine (Chapters 11 and 12), troxacitabine (Chapter 9), clofarabine, which
was approved recently for acute leukemia (Chapter 7), and ara-G (Chapter 10). Two
additional chapters deal with prodrug design (Chapter 15) or the novel class of
L-nucleosides (Chapter 8).
Modern drug development tends to focus on specific targets, thereby neglecting
that, in order to be effective, a drug needs to be taken up by the body and transported
to the malignant tissues. A proper understanding of pharmacokinetics and
pharmacodynamics of deoxynucleoside analogs is indispensable to their admini-
stration (Chapter 14). Also, pharmacogenomics, specific genetic properties of a
tumor or a subject, determines whether a tumor will be sensitive to a drug and
whether a patient will tolerate a drug. Proper knowledge of a patient’s pharmaco-
genomics profile enables individualized treatment, as described in chapters on
specific drugs.
Deoxynucleoside analogs can be considered ideal compounds to be combined
with other drugs, either with classical cytotoxic agents or with novel so-called targeted
agents such as cell cycle-directed compounds, various protein kinase inhibitors, and
angiogenesis inhibitors. These applications are also described in specific chapters,
while a specific chapter is dedicated to the excellent radiosensitizing properties of
deoxynucleoside analogs (Chapter 13). The last chapter focuses on a novel
application of a deoxynucleoside analog, the use of 3'-deoxy-3'-fluorothymidine as
Preface vii
an active tracer in PET with the potential to replace fluorodeoxyglucose in specific
applications (Chapter 17).
ThroughoutDeoxynucleoside Analogs in Cancer Therapy, the focus is on novel
aspects of deoxynucleoside analogs in the clinical context, as well as on unexpected
targets of these compounds, such as their specific activity against cell cycle-
dependent kinases or oncogenes. Modern targeted cancer chemotherapy aims to be
more specific than in the past, but it has now been recognized that inhibition of just
one target often enables the cell to find another pathway, bypassing this inhibition.
Current knowledge of deoxynucleoside analogs has already led to successful
combinations with novel targeted agents that prevent inhibition of one target from
being bypassed by simultaneous activation of another. Future research in this field
should use this knowledge to design rational combinations aimed at inhibiting various
cellular signaling pathways, enhancing apoptotic pathways, or combining inhibition
of various targets. Deoxynucleoside Analogs in Cancer Therapy has been designed
specifically to facilitate such an interaction between various fields.
Godefridus J. Peters, PhD
C
ONTENTS
Preface .....................................................................................................v
Contributors............................................................................................xi
1 Nucleoside Transport Into Cells: Role of Nucleoside Transporters SLC28
and SLC29 in Cancer Chemotherapy
Marçal Pastor-Anglada and F. Javier Casado.....................................1
2 The Role of Deoxycytidine Kinase in DNA Synthesis
and Nucleoside Analog Activation
Maria Staub and Staffan Eriksson......................................................29
3 Deoxynucleoside Kinases and Their Potential Role in Deoxynucleoside
Cytotoxicity
^
Birgitte Munch-Petersen and Jure Piskur..........................................53
4 Nucleotidases and Nucleoside Analog Cytotoxicity
Sally Anne Hunsucker, Beverly S. Mitchell, and Jozef Spychala.....81
5 Pumping Out Drugs: The Potential Impact of ABC Transporters
on Resistance to Base, Nucleoside, and Nucleotide Analogs
Piet Borst and Peter Wielinga............................................................109
6 Cytosine Arabinoside: Metabolism, Mechanisms of Resistance,
and Clinical Pharmacology
Isabelle Hubeek, Gert-Jan L. Kaspers, Gert J. Ossenkoppele,
and Godefridus J. Peters................................................................119
7 Clofarabine: Mechanisms of Action, Pharmacology,
and Clinical Investigations
Varsha Gandhi and William Plunkett...............................................153
8 L-Nucleosides as Chemotherapeutic Agents
Giuseppe Gumina, Youhoon Chong, and Chung K. Chu................173
9 Troxacitabine (Troxatyl™):A Deoxycytidine Nucleoside Analog
With Potent Antitumor Activity
Henriette Gourdeau and Jacques Jolivet..........................................199
10 9-(cid:69)-D-Arabinofuranosylguanine
Sophie Curbo and Anna Karlsson.....................................................215
ix
x Contents
11 Gemcitabine: Mechanism of Action and Resistance
Andries M. Bergman and Godefridus J. Peters................................225
12 Clinical Activity of Gemcitabine
as a Single Agent and in Combination
Judith R. Kroep, Godefridus J. Peters, and Robert A. Nagourney ......253
13 Nucleoside Radiosensitizers
Donna S. Shewach and Theodore S. Lawrence................................289
14 NONMEM Population Models of Cytosine Arabinoside
and Fludarabine Phosphate in Pediatric Patients With Leukemia
Vassilios I. Avramis............................................................................331
15 The cycloSal-Nucleotide Delivery System: Development
of Chemical Trojan Horses as Antiviral Agents
Chris Meier, Jan Balzarini, and Astrid Meerbach...........................353
16 Purine and Pyrimidine-Based Analogs and Suicide Gene Therapy
Zoran Gojkovic and Anna Karlsson..................................................403
17 3'-Deoxy-3'-Fluorothymidine as a Tracer of Proliferation
in Positron Emission Tomography
Wieteke G. E. Direcks, Adriaan A. Lammertsma,
and Carla F. M. Molthoff..............................................................441
Index ....................................................................................................463