Table Of ContentARACHIDONIC ACID METABOLISM AND
TUMOR PROMOTION
PROSTAGLANDINS, LEUKOTRIENES, AND CANCER
Series Editors: Kenneth V. Honn and Lawrence J. Marnett
Wayne State University &hool of Medicine
Detroit, Michigan
W.E.M. Lands, ed.: Biochemistry of Arachidonic Acid Metabolism. 1985. ISBN
0-89838-717-5.
L.l. Marnett, ed.: Arachidonic Acid Metabolism and Tumor Initiation. 1985. ISBN
0-89838-729-9.
S.M. Fischer and T.J. Slaga, eds.: Arachidonic Acid Metabolism and Tumor Pro
motion. 1985. ISBN 0-89838-724-8.
1.S. Goodwin, ed.: Prostaglandins and Immunity. 1985. ISBN 0-89838-723-X.
ARACHIDONIC ACID METABOLISM
AND TUMOR PROMOTION
edited by
Susan M. Fischer
and
Thomas J. Slaga
The University oj Texas System Cancer Center
Smithville, Texas
.....
"
Martinus Nijhoff Publishing
a member oj the Kluwer Academic Publishers Group
Boston/Dordrecht/Lancaster
Distributors for North America:
Kluwer Academic Publishers
190 Old Derby Street
Hingham, MA 02043
Distrihutors for all other countries:
Kluwer Academic Publishers Group
Distribution Centre
P.O. Box 322
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The Netherlands
Library of Congress Cataloging in Publication Data
Main entry under title:
Arachidonic acid metabolism and tumor promotion.
(Prostaglandins, leukotrienes, and cancer)
Includes bibliographies and index.
I. Cocarcinogenesis. 2. Arachidonic acid
Metabolism. I. Fischer, Susan M. II. Siaga,
Thomas]. III. Series. [DNLM: 1. Arachidonic
Acids-metabolism. 2. Neoplasms-etiology.
QU 90 A658]
RC268.52.A73 1985 616.99 '4071 85-4968
ISBN-13 :978-1-4612-9631-7 e-ISBN-13 :978-1-4613-2605-2
DOl: 10.1007/978-1-4613-2605-2
Copyright © 1985 by Martinus Nijhoff Publishinl, Boston
Softcover reprint of the hardcover 1s t edition 1985
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
transmitted in any form or by any means, mechanical, photocopying, recording, or otherwise,
without written permission of the publisher, Martinus Nijhoff Publishing, 190 Old Derby Street,
Hingham, Massachusetts 02043.
CONTENTS
CONTRIBUTORS vi
FOREWORD vii
PREFACE viii
INTRODUCTION 1
1. ARACHIDONIC ACID METABOLISM IN THE SKIN 4
Vincent A. Ziboh
2. ARACHIDONIC ACID METABOLISM AND
TUMOR PROMOTION 21
Susan M. Fischer
3. PROSTAGLANDINS, EPIDERMAL HYPERPLASIA AND
SKIN TUMOR PROMOTION 49
Gerhard Furstenberger and Friedrich Marks
4. EFFECTS OF PHORBOL ESTERS ON PHOSPHOLIPID
METABOLISM IN VITRO 73
Philip W. Wertz
5. TUMOR PROMOTING PHORBOL ESTERS MAY AFFECT
CELL MEMBRANE SIGNAL TRANSMISSION BY
PROTEIN KINASE 101
Curtis L. Ashendel
6. ACTIVE OXYGEN AND PROMOTION 131
Peter A. Cerutti
7. POSSIBLE INVOLVEMENT OF ARACHIDONATE
PRODUCTS IN TUMOR PROMOTER INHIBITION OF
CELL-CELL COMMUNICATION 169
James E. Trosko, C. Aylsworth, C. Jone and C. C. Chang
8. PROTEASES AND CYCLIC NUCLEOTIDES 199
Sidney Belman and Seymour J. Garte
PERSPECTIVES 255
Thomas J. Siaga and Susan M. Fischer
INDEX 259
v
CONTRIBUTORS
CURTIS L. ASHENDEL SEYMOUR J. GARTE
Department of Medicinal Chemistry New York University Medical Center
Purdue University Department of Environmental Medicine
Pharmacy Building 550 First Avenue
West Lafayette, Indiana 47907 New York, New York 10016
CHARLESF.AYLSWORTH CYRENIUS JONE
Department of Anatomy Department of Pediatrics and Human
Michigan State University Development
East Lansing, Michigan 48824 B240 Life Science Building
Michigan State University
SIDNEY BELMAN East Lansing, Michigan 48824
Institute of Environmental Medicine
New York University Medical Center FRIEDRICH MARKS
550 First Avenue German Cancer Research Institute
New York, New York 10016 Institute of Biochemistry
D-6900 Heidelberg
PETER A. CERUTTI WEST GERMANY
Department of Carcinogenesis
Swiss Institute for Experimental THOMAS J. SLAGA
Cancer Research The University of Texas
Ch. de Boveresses System Cancer Center
CH-I066 Epalinges/Lausanne Science Park-Research Division
SWITZERLAND Post Office Box 389
Smithville, Texas 78957
CHIA CHENG CHANG
Department of Pediatrics and JAMES E. TROSKO
Human Development Department of Pediatrics and
B240 Life Science Building Human Development
Michigan State University B240 Life Science Building
East Lansing, Michigan 48824 Michigan State University
East Lansing, Michigan 48824
SUSAN M. FISCHER
The University of Texas PHILIP W. WERTZ
System Cancer Center University of Iowa
Science Park-Research Division Iowa City, Iowa 52242
Post Office Box 389
Smithville, Texas 78957 VINCENT A. ZIBOH
Department of Dermatology
GERHARD FURSTENBERGER TB-192
German Cancer Research Institute University of California School
Institute of Biochemistry of Medicine
D-6900 Heidelberg Davis, California 95616
WEST GERMANY
vi
FOREWORD
Prostaglandins, Leukotrienes, and Cancer is a multi-volume series that will
focus on an emerging area of cancer research. In 1968, R.H. Williams first
reported that elevated prostaglandin levels are present in human medullary car
cinoma. Since that time, the concept that arachidonic acid metabolites may be in
volved in cancer has expanded to include every aspect of the disease from cell
transformation through metastasis.
Prostaglandins and leukotrienes are generic terms used to describe a family of
bioactive lipids produced from unsaturated fatty acids (principally from
arachidonic acid) via the cyclooxygenase and lipoxygenase pathways, respec
tively. Cyclooxygenase products consist of diverse products such as prosta
glandin E2 (POE2), prostacyclin (POI2) and thromboxane A2 (TXA2), whereas
lipoxygenase products consist of hydroperoxy fatty acids and mono-, di- and
tri-hydroxy acids including leukotrienes. The precursor fatty acids for the
cyclooxygenase and lipoxygenase pathways are present in cellular phospholipids.
This finding established an important control point in their biosynthesis-the
release of substrate. This occurs in response to numerous stimuli that act at the
cell surface. Dr. Bengt Samuelsson's extensive study of the metabolism of pros
taglandins indicated that they are rapidly inactivated on a single pass through
pulmonary circulation. Thus, they cannot act as circulating hormones and appear
to be made on demand in or in the vicinity of target tissues leading to the concept
that prostaglandins are local hormones or autocoids.
Altered production, qualitative and/or quantitative, of prostaglandins and
leukotrienes has been implicated in the development of a number of disease states
(e.g., atherosclerosis, inflammatory diseases, asthma). Evidence has been
accumulating in the literature suggesting that prostaglandins and leukotrienes
may stimulate or inhibit various steps in the complex etiology of cancer, i.e.,
steps in the progression from a transformed cell to a metastatic tumor. The initial
volumes in this series will examine the roles of prostaglandins and leukotrienes in
tumor initiation, tumor promotion, tumor cell growth and differentiation, tumor
immunity, tumor metastasis and cancer therapy. We hope as this field of cancer
research develops that this series, Prostaglandins, Leukotrienes, and Cancer, will
provide a forum within the framework of current evidence for the synthesis of
new hypotheses and discussion of controversial issues.
Kenneth V. Honn
Lawrence J. Marnett
vii
PREFACE
In reviewing varied topics of scientific investigations in the broad field of car
cinogenesis, one cannot help but note the increased interest in tumor promotion
and prostaglandins that has developed and the rapid advancements which are
taking place in these areas. The importance of both inflammation and cell pro
liferation in tumor promotion suggested to researchers the critical involvement of
prostaglandins (arachidonic acid cascade) in the process of tumor promotion. An
apparent marriage of sorts has taken place between these two important areas of
investigation with the resulting research providing some notable results that are
aiding in the unraveling of the mysteries of cancer.
This volume, "Arachidonic Acid Metabolism and Tumor Promotion," is one
of a series covering a wide range of research on the importance or role of
arachidonic acid metabolites on the induction and treatment of cancer. Included
in this volume are chapters that cover both arachidonic acid metabolism in the
skin and the role(s) of arachidonic acid metabolites in skin tumor promotion and
promoter-induced inflammation and epidermal hyperplasia. The effects of
phorbol ester tumor promoters on phospholipid metabolism in vitro are ex
amined and the effects tumor promoting phorbol esters may exert on cell mem
brane signal transmission by protein kinase C are presented. In another chapter,
the relationship between active oxygen or more broadly the prooxygen state and
promotion is presented. The possible involvement of arachidonate products in
tumor promoter inhibition of cell-cell communication is covered and finally a
chapter on proteases and cyclic nucleotides is included because of their effect on
and relationship to the arachidonic acid cascade.
It is the general aim of this volume to carefully examine the scientific relation
ship between arachidonic acid metabolism and tumor promotion. Various
inhibitors of arachidonic acid metabolism may very well be useful chemopreven
tive agents against cancer.
It is indeed hoped that this volume will encourage further scientific investiga
tions and therefore a better understanding of the role of arachidonic acid
metabolites in tumor promotion. Of interest to all scientists involved in medical
research especially related to cancer, it will also be of special interest to phar
macologists, biochemists, cell biologists, molecular biologists, pathologists, and
toxicologists.
viii
INTRODUCTION
S.M. Fischer and T.J. Slaga
The importance of prostaglandins, thromboxanes, prostacyclin,
hydroperoxy fatty acids and leukotienes in cancer can no longer be
considered simply a possibility; work in recent years has clearly
indicated such a reality. These compounds are produced by the oxi
dation of 20 carbon fatty acids such as arachidonic acid (see Figure
1). The level of involvement of these eicosanoids, the term applied
to all arachidonate metabolites, in cancer occurs at all levels from
carcinogen metabolism to tumor promotion to the rate of proliferation
of tumors to the i nteracti on between the tumor and hos t to the meta
static potential of tumors. This volume, one of a series intended
to cover this spectrum of the disease we call cancer, is devoted to
one aspect, tumor promotion.
The transformation of a normal cell to a cancerous one is a
complex process which can be induced by any of a variety of reagents,
including viruses, radiation and chemicals. Each of these agents can
cause an alteration in the genome and/or the rate of expression of
the genetic material. This irreversible step is called initiation.
Such changes may not be manifested in tumors if the dose or level of
initiator is low. Subsequent repeated exposure to noncarcinogenic
compounds called promoters, however, results in tumors, the phenotypic
expression of the initiation event. One of the best studied models
in this regard is the two-stage carcinogenesis model in mouse skin.
The promoter most commonly used, and one of the most potent so far
identified, is tetradecanoylphorbol acetate (TPA or PMA); its mechan
ism of action is not completely understood, however. Application of
TPA as well as of other promoters to mouse skin triggers numerous
1
2
morphological and biochemical events including such responses as an
increased phospholipid metabolism, an increase in arachidonic acid release
and an elevation of prostaglandin levels which are described in detail in
this volume. These events may contribute to the intense inflammation
produced by TPA. Eicosanoids are further implicated in the promotion
process by the findings that inhibitors of various parts of the arachidonic
acid cascade can modulate the tumor response. Because several of the same
inhibitors effectively inhibit specific TPA-induced events, such as
ornithine decarboxylase activity, the role of arachidonate metabolites in
promotion is clearly implicated.
The work described in this volume, while primarily using TPA as the
prototype promoter and frequently using mouse skin as the model, has far
reaching implications. The phenomenon of tumor promotion has been de
scribed for other organs (e.g. liver, bladder, esophagus), other types of
compounds (e.g. benzoyl peroxide, anthralin, teleocidin, saccharin) and
other species, most notably man. The ultimate significance in under
standing the mechanism of tumor promotion, as well as any other aspect of
the neoplastic process, lies in the possibility that cancer can be pre
vented by intervening in the complex series of events that occur in
carcinogenesis. For this reason the role of archidonate metabolites in
physiological and pathological states is under increasingly more inten
sive investigation.
