Combination cancer therapy : modulators and potentiators

295 Pages·2005·4.8 MB·english

by  Gary K Schwartz

C C T
OMBINATION ANCER HERAPY
C D D
ANCER RUG ISCOVERY
D
AND EVELOPMENT
B A. T , S E
EVERLY EICHER ERIES DITOR
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and Potentiators, edited by Gary K. Preclinical Screening, Clinical Trials,
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Hawk, and Caroline C. Sigman, 2005 Chemoradiation in Cancer Therapy,
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C C
OMBINATION ANCER
T
HERAPY
M P
ODULATORS AND OTENTIATORS
Edited by
G K. S ,
ARY CHWARTZ MD
Division of Solid Tumor Oncology, Department of Medicine,
Memorial Sloan-Kettering Cancer Center, New York, NY
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Library of Congress Cataloging-in-Publication Data
Combination cancer therapy : modulators and potentiators / edited by Gary K. Schwartz.
p. ; cm. -- (Cancer drug discovery and development)
Includes bibliographical references and index.
ISBN 1-58829-200-2 (alk. paper)
1. Cancer--Chemotherapy. 2. Apoptosis. 3. Cancer--Treatment.
[DNLM: 1. Neoplasms--drug therapy. 2. Drug Therapy, Combination.
QZ 267 C731 2005] I. Schwartz, Gary K. II. Series.
RC271.C5C615 2005
616.99'4061--dc22
2004010543
P
REFACE
The concept of combining chemotherapeutic agents to increase cytotoxic
efficacy has evolved greatly over the past several years. In the past, the rationale
for combination chemotherapy centered on attacking different biochemical tar-
gets, overcoming drug resistance in heterogenous tumors, and increasing the
dose-density of combination chemotherapy to take advantage of tumor growth
kinetics. The overall goal was to improve clinical efficacy with acceptable clini-
cal toxicity. We are now moving to a new generation of drug therapies. An
understanding of the molecular basis of tumor cell growth and differentiation has
resulted in the identification of new targets for cancer therapy. These targets
range from proteins that regulate the cell cycle to cell-surface receptors that
mediate signal transduction events. However, despite promising preclinical
activity as single agents, early clinical trials with these drugs have proven disap-
pointing, with rare clinical responses. This may be explained by the fact that
these agents are not classic cytotoxic drugs. Instead, the interruption of intrac-
ellular signals is capable of inducing growth arrest with minimal cell death.
Recent studies indicate that these new agents are potent potentiators of chemo-
therapy-induced apoptosis. It is now apparent that the future clinical develop-
ment of these molecularly targeted therapies will depend on the modulation of
molecular events that will enhance the efficacy of our classic cytotoxic drugs.
Therefore, as these drugs become part of our clinical programs, it will be essential
to understand how to combine them with traditional chemotherapy. For example,
it is now apparent that the sequence of administration of cyclin-dependent kinase
inhibitors relative to chemotherapy can either enhance or antagonize the chemo-
therapeutic effect. These sequence-dependent effects can be explained by cell
cycle perturbations, or by pharmacodynamic interactions between the agents in
combination. An understanding of these drug interactions will be critical for the
successful introduction of these new agents into traditional clinical use. Thus, it
does not appear that we will be abandoning traditional cytotoxic agents for the
new molecularly based approach to oncology. Rather, current studies indicate
that chemotherapy and cytotoxic agents will continue to serve as a foundation
upon which the next generation of new small molecules will be added as modu-
lators and potentiators. In Combination Chemotherapy: Modulators and Poten-
tiators, we focus on novel drug combinations with new agents that hold the most
promise for the future of medical oncology. They run the gamut of targeted
therapies against cell surface receptors (EGF-R and HER2), the cell cycle (the
CDKs), signal transduction events (PKC and NF-(cid:80)B), apoptosis (bcl-2), as well
v
vi Preface
as novel targeted therapies in ovarian cancer, hematologic diseases, and breast
cancer. The emphasis is on new translational approaches that are being moved
from the laboratory bench top to the patient’s bedside for the future treatments
in cancer therapy.
Gary K. Schwartz, MD
C
ONTENTS
Preface...............................................................................................................v
Contributors......................................................................................................ix
1 Targeting of the EGFR As a Modulator
of Cancer Chemotherapy.....................................................................1
Jose Baselga
2 Cyclin-Dependent Kinase Inhibitors
in Combination Chemotherapy..........................................................27
Manish A. Shah and Gary K. Schwartz
3 Development of Protein Kinase C and Cyclin-Dependent
Kinase Inhibitors As Potentiators of Cytotoxic Drug Action
in Leukemia........................................................................................61
Steven Grant
4 Carboxyamidotriazole, an Inhibitor of Nonvoltage-Operated
Calcium Entry: Single-Agent and Combination Therapy
for Ovarian Carcinoma.......................................................................89
Chad M. Michener and Elise C. Kohn
5 Targeted(cid:70)-Particle Therapy: A Rational Approach to Drug
Development in Hematologic Diseases and Solid Tumors.............107
John M. Burke, David A. Scheinberg, and Joseph G. Jurcic
6 Pharmacological Modulation of Fluoropyrimidines:
Building on the Lessons of the Past.................................................133
Owen A. O’Connor
7 Development of Inhibitors of HER2 With Taxanes:
New Directions in Breast Cancer Therapy.....................................175
Shanu Modi, Monica N. Fornier, and Andrew D. Seidman
8 Targeting NF-(cid:80)B to Increase the Activity of Cisplatin
in Solid Tumors................................................................................197
Don S. Dizon, Carol Aghajanian, X. Jun Yan,
and David R. Spriggs
9 Combinations of Chemotherapy and G3139,
an Antisense Bcl-2 Oligonucleotide................................................209
Luba Benimetskaya, Sridhar Mani, and C. A. Stein
vii
viii Contents
10 Use of Animal Models to Evaluate Signal Transduction
Inhibitors As Modulators of Cytotoxic Therapy.............................231
Beverly A. Teicher
Index..............................................................................................................277
C
ONTRIBUTORS
CAROL AGHAJANIAN,MD • Developmental Chemotherapy Service, Memorial
Sloan-Kettering Cancer Center, New York, NY
JOSE BASELGA,MD • Vall d'Hebron University Hospital, Universidad
Autonoma, Barcelona, Spain
LUBA BENIMETSKAYA,PhD • Department of Medical Oncology/Medicine,
Montefiore Medical Center, Albert Einstein College of Medicine, Bronx,
New York, NY
JOHN M. BURKE,MD • Department of Medicine, Memorial Sloan-Kettering
Cancer Center, New York, NY
DON S. DIZON,MD • Director of Medical Oncology, Program in Women’s
Oncology, Women & Infants’ Hospital, Brown Medical School,
Providence, RI
MONICA N. FORNIER,MD • Breast Cancer Service, Memorial Sloan-Kettering
Cancer Center, New York, NY
STEVEN GRANT,MD • Department of Medicine, Medical College of Virginia,
Virginia Commonwealth University, Richmond, VA
JOSEPH G. JURCIC,MD • Hematology Service, Memorial Sloan-Kettering
Cancer Center, New York, NY
ELISE C. KOHN,MD • Molecular Signaling Section, Laboratory of Pathology,
National Cancer Institute, Bethesda, MD
SRIDHAR MANI,MD • Department of Medical Oncology/Medicine, Montefiore
Medical Center, Albert Einstein College of Medicine, Bronx, New York, NY
CHAD M. MICHENER,MD • Molecular Signaling Section, Laboratory
of Pathology, National Cancer Institute, Bethesda, MD
SHANU MODI,MD • Breast Cancer Service, Memorial Sloan-Kettering Cancer
Center, New York, NY
OWEN A. O’CONNOR,MD,PhD • Lymphoma and Developmental Chemotherapy
Services, Division of Hematologic Oncology, Memorial Sloan-Kettering
Cancer Center, New York, NY
DAVID A. SCHEINBERG,MD,PhD • Experimental Therapeutics Center, Leukemia
Service, Memorial Sloan-Kettering Cancer Center, New York, NY
ix