Alternative Mechanisms of Multidrug Resistance in Cancer

287 Pages·1995·20 MB·English

by  John A. Kellen (auth.), John A. Kellen (eds.)

Alternative Mechanisms
of Multidrug Resistance
in Cancer
Cover: A schematic, simplified presentation of various cellular drug
resistance mechanisms. By John A. Kellen and Patsy Cunningham.
Alternative Mechanisms
of Multidrug Resistance
in Cancer
JohnA. Kellen
Editor
Birkhauser
Boston • Basel • Berlin
John A. Kellen
Sunnybrook Health Science Center
University of Toronto
Toronto, Canada M4N 3M5
Library of Congress Cataloging-in-Publication Data
Mechanisms and reversal of multi drug resistance in cancer : the other
alternatives / John A. Kellen, editor.
p. cm.
Includes bibliographical references and index.
ISBN 0-8176-3775-3 (h : alk. paper). -- ISBN 3-7643-3775-3 (h
: alk. paper). .
1. Drug resistance in cancer cells. 2. Multidrug resistance.
I. Kellen, John A.
[DNLM: 1. Neoplasms--drug therapy. 2. Drug Resistance, Multiple-
-physiology. 3. Antineoplastic Agents, Combined--pharmacology. QZ
RC271.C5M42 1995 95-1582
616.99'4061--dc20 CIP
DNLMJDLC
for Library of Congress
Birkhiiuser $ ®
© 1995 Birkhauser Boston
Softcover reprint of the hardcover 1s t edition 1995
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U.S.A.
Camera-ready text prepared by the editor.
ISBN-13: 978-1-4615-9854-1 e-TSBN-13: 978-1-4615-9852-7
DOl: 10.1 007/978-1-4615-9852-7
CONTENTS
Preface .................................! •••••••••••••••••••••••••••••• vii
List of Contributors .................................................... xi
1. Mechanisms of Multidrug Resistance
J.A. Kellen ...................................................... 1
2. The Role of Glutathione S-'Transferases in Drug Resistance
W. T. Bellamy ................................................... 31
3. Pharmacology of Drug 'Transport in Multidrug Resistant
Tumor Cells
H.J. Broxterman and C.H. Versantvoort ......................... 67
4. The Multidrug Resistance-Associated Protein MRP
D. Fan, D.R. Bielenberg, Y.F. Wang, R. Radinsky,
and P.J. Beltran ................................................ 81
5. Topoisomerases in Multidrug Resistance
T. Utsugi, C.E. Herzog, and D. Fan ............................. 95
6. Genotoxicity of Topoisomerase II Inhibitors-Consequences
of Chemotherapy
F. Gieseler ..................................................... 121
7. A Distinctive Multiple Drug Resistance Phenotype in
Tumor Cells Exposed to X-Irradiation
B. T. Hill ....................................................... 135
8. Taxoids and Multidrug Resistance
R.A. Newman and D. Fan ...................................... 153
9. The Contribution of Protein Kinase C to Multiple
Drug Resistance in Cancer
C.A. 0 'Brian, N.E. Ward, K.P. Gupta, and K.R. Gravitt ....... 173
10. Bcl-2 and Chemoresistance in Cancer
J.C. Reed ..................................................... 191
vi Contents
11. Molecular Interrelationships in Multidrug Resistance
J.A. Kellen .. ................................................. 215
12. Platinum Resistance in Human Carcinomas
H. Ishida, H. Kijima, Y. Ohta, M. Kashani-Sabet,
and K. J. Scanlon ......... .................................... 225
Perspectives
J.A. Kellen .......................................................... 265
Conclusions
J.A. Kellen .......................................................... 275
Index ................................................................ 279
PREFACE
Nullius in verba. .. Truth will be tested
not by words. Horace (Epistles)
Few read introductions except for book reviewers, who want to take a
shortcut and avoid reading the book itself. However, tradition requires
that the preface make public why the book was written at all (this is not
supposed to include powerful reasons such as augmenting the ego of the
editor and authors). Frequently, the inflationary tendency to publish in
verbose length is in conflict with market forces and interest.
No doubt, multidrug resistance is a "fashionable" topic, but there are
many fashions displayed on the cat-walk of scientific literature. One can
rationalize that the forces driving our concern with multi drug resistance
reflect the frustration of pharmaceutical companies and oncologists alike:
as soon as a new anticancer drug enters clinical trials, cancer cells start
eluding extinction with their elaborate and successful mechanisms. Many
grants have been awarded and spent, only to confirm the futility of our
efforts to defeat this cellular Darwinism. Our medical and scientific training
makes it hard, if not impossible, to accept that the survival of a malignant
cell, alone or as part of a tissue, is part of the continuance of life. Since
exposure to noxious and lethal substances is unavoidable, cells have been
forced to develop a multitude of mechanisms to prevent entry or accelerate
exit of such materials from intracellular space. The final result from these
complex actions is a decrease of intracellular concentrations to tolerable
levels, allowing survival of the cell. Cancer cells are no exception; of course,
this becomes most undesirable when the cell is malignant and its good
housekeeping wards off the effect of cytotoxic drugs.
It is an accepted truism that once we understand the cause of an event,
we may prevent, circumvent, or reverse it. Medicine is based on this gen-
eral tenet. The phenomenon of cross-resistance, whether innate or selected
by exposure to one or more drugs, is the result of numerous mechanisms
operating in concert; they depend on the level and length of exposure, ge-
netic make-up of the cancer cell, size of the cell population, characteristics
of the inducing agent, level of oxygenation, intra- and extracellular pH and
probably on many more unknown factors. We are only at the beginning
of our insight into this complexity; for every complex question, there is
almost certainly a simple answer that is almost always wrong. There are
no simple answers for MDR. All biological systems are both capable to de-
fend themselves by the production of toxic substances and possess age-old
mechanisms for defending themselves against these. MDR is a problem
created by a mixture of variables that affect the outcome of chemotherapy
viii Preface
in different and often unpredictable ways. For the clinical oncologist, resis-
tance is synonymous with the fate of the individual patient: what happens
to the tumor mass and how it responds to treatment.
Increasing insight into the vulnerability of malignant cells has led to
the design of perfectly tailored cytotoxic substances, expected to cause
reasonably selective extinction of the cancer cell population. Yet, even
the best of such fits allows a critical number of cells to escape and regrow
in eventually fatal numbers, as the result of cumulative, cooperative cel-
lular defenses. Perhaps the first stepping stone in our understanding of
such defense mechanisms has been the recognition of P-glycoprotein as a
general efflux pump. This may be o~e of the primordial instruments for
turfing out unwanted guests, but it does not fulfill our expectations for a
single "deus ex machina" which provides all the answers and solves all the
problems. P-glycoprotein is considered by some as a "first line of defense,"
appearing very early in the hierarchy of defense mechanisms, as a normal
response to foreign agents and hence inevitable in many, but not all tu-
mors. Introduction of the apparently synonymous terminology: MDR for
multidrug resistance and mdrl for the gene expressing P-glycoprotein, is
causing some confusion; MDR in cancer can be caused by a multitude of
mechanisms and is a vague term describing the ability of tumor cells to
repair sublethal damage caused by structurally unrelated cytotoxic drugs.
Acquired multidrug resistance is being extensively studied in rodent and
human cell lines, with single or multistep selection, by one or more drugs
or other inducers. In vitro conditions are ideal for "clean" experiments
with a minimum of variables. Clinical studies are more difficult, if not
impossible, to compare and evaluate since they differ in treatment proto-
cols, demography as well as methodology and criteria for positivity of the
MDR phenotype.
MDR predominantly caused by P-glycoprotein has been coined as
"classical," again a term which should be disputed. Binding to P-glyco-
protein (as evidenced by photolabelling) is not always synonymous with
transport across biomembranes, but reduced drug accumulation in non-
Pgp-MDR cells is less well understood. Preoccupation with a single so-
lution has led to the neglect of other explanations. Even more simplistic
is the trend to use the term "atypical MDR" for resistance mechanisms
involving Topoisomerase II only. Finally, there is a growing grab-bag filled
with "non P-glycoprotein mediated" MDR which ranges from other mem-
brane proteins belonging to the ATP-binding cassette (ABC) superfamily
to a variety of detoxifying mechanisms, enzymatic and other.
The cooperative effort represented by this book expressed our feel-
ings that we have reached a critical mass of information: within the un-
comfortable framework of inherent instability characteristic for the cancer
cell, we must accept the continuously adapting and changing complexity of
resistance. Some important and some perhaps less important factors have
been examined and evaluated. At present, we can not predict which single
Preface ix
mechanism will playa leading role - if there is a universal leading role at
all; only the passage of time will provide new perspectives.
I had the good fortune to persuade many eminent scientists in the
MDR scene to come forward with state of the art reviews in an apparently
heterogeneous field. This heterogeneity should not come as a surprise, but
as a warning. If clinical researchers wish to more effectively plan treatment
with drugs and drug combinations able to circumvent defense mechanisms,
they must learn to understand the molecular basis of drug resistance. The
gap in our interpretation and application of data are evident and may
direct the curious to further analytic and synthetic travail; comprehending
the whole as more than the sum of its parts. To quote Galileo: We must
look at what others have looked before and see it as no one has seen it
before ...
John A. Kellen
August 1994
LIST OF CONTRIBUTORS
William T. Bellamy, Ph.D., Arizona Health Science Center, Tucson,
Arizona, USA
Pedro J. Beltran, University of Texas M.D. Anderson Cancer Center,
Houston, Texas, USA
Diane R. Bielenberg, B.S., University of Texas M.D. Anderson Cancer
Center, Houston, Texas, USA
Henk J. Broxterman, Ph.D. Academ. Ziekenhuis, VU Amsterdam,
Amsterdam, The Netherlands
Dominic Fan, Ph.D., University of Texas M.D. Anderson Cancer Center,
Houston, Texas, USA
Frank Gieseler, M.D., Mediz. Poliklinik de Universitiit Wiirzburg, Wiirz-
burg, Germany
Karen R. Gravitt, M.Sc., University of Texas M.D. Anderson Cancer
Center, Houston, Texas, USA
Krishna P. Gupta, Ph.D., University of Texas M.D. Anderson Cancer
Center, Houston, Texas, USA
Cynthia E. Herzog, M.D., University of Texas M.D. Anderson Cancer
Center, Houston, Texas, USA
Bridget T. Hill, Ph.D., Ctr. de Recherche Pierre Fabre, Castres, France
Hironori Ishida, M.D., City of Hope Natl. Med. Ctr., Duarte, California,
USA
Mohamed Kashani-Sabet, M.D., City of Hope Natl. Med. Ctr., Duarte,
California, USA
John A. Kellen, M.D., Ph.D., Sunybrook Health Science Centre, Univer-
sity of Toronto, Toronto, Canada
Hiroshi Kijima, M.D., City of Hope Natl. Med. Ctr., Duarte, California,
USA
Robert A. Newman, University of Texas M.D. Anderson Cancer Center,
Houston, Texas, USA
Catherine A. O'Brian, Ph.D., University of Texas M.D. Anderson Can-
cer Center, Houston, Texas, USA
Yukinori Ohta, Ph.D., City of Hope Natl. Med. Ctr., Duarte, California,
USA