Protease Inhibitors as Cancer Chemopreventive Agents

321 Pages·1993·18.87 MB·English

by  Elizabeth Fontham

Protease Inhibitors as
Cancer Chemopreventive
Agents
Protease Inhibitors as
Cancer Chemopreventive
Agents
Edited by
Walter Troll
New York University Medical Center
New York, New York
and
Ann R. Kennedy
University of Pennsylvania School of Medicine
Philadelphia, Pennsylvania
Springer Science+Business Media, LLC
Llbrary of Congress Cataloglng-ln-Publlcatlon Data
Protease lnhlbitors as cancer chemopreventive agents I edited by
Walter Troll, Ann R, Kennedy.
p. cm.
Inc I udes b 1b li ograph 1 ca I references and 1 ndex.
ISBN 978-1-4613-6249-4 ISBN 978-1-4615-2882-1 (eBook)
DOI 10.1007/978-1-4615-2882-1
1. Sancer--Chemoprevention. 2. Proteolytlc enzyme lnhlbltors
-Therapeutic use. 1. Troll, Walter. II. Kennedy, Ann R.
[DNLM, 1. Protease Inhibltors--therapeutic use. 2. Protease
Inhlbitors--metabolism. 3. Neoplasms--preventlon & control. OU
138 P9885 1993J
RC288.15.P77 1993
818.99·405--dc20
DNLM/DLC
for Library of Congress 93-24959
CIP
ISBN 978-1-4613-6249-4
© 1993 Springer Science+Business Media New York
Originally published by Plenum Press New York in 1993
Softcover reprint of the hardcover 1s t edition 1993
AII rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
Contributors
Takaaki Aoyagi Institute of Microbial Chemistry, Shinagawa-ku, Tokyo 141,
Japan
Sila Banerjee Department of Obstetrics and Gynecology, New York Univer-
sity Medical Center, New York, New York 10016
Anne H. Bates Western Regional Research Center, Agricultural Research
Service, U.S. Department of Agriculture, Albany, California 94710
Paul C. Billings Department of Radiation Oncology, University of Pennsyl-
vania School of Medicine, Philadelphia, Pennsylvania 19104
Yehudith Birk Department of Biochemistry and Human Nutrition, Faculty of
Agriculture, The Hebrew University of Jerusalem, Rehovot 76100, Israel
Donald E. Bowman Departments of Biochemistry and Molecular Biology,
School of Medicine, Indiana University, Indianapolis, Indiana 46202-5122
David L. Brandon Western Regional Research Center, Agricultural Research
Service, U.S. Department of Agriculture, Albany, California 94710
Ann F. Chambers The London Regional Cancer Centre, University of West-
ern Ontario, London, Ontario, Canada N6A 4L6
Janice D. Chang Department of Biology, Massachusetts Institute of Tech-
nology, Cambridge, Massachusetts 02139
Rita Colella Department of Biological Sciences, Rutgers University, Pis-
cataway, New Jersey 08855. Present address: Department of Anatomical
Sciences and Neurobiology, University of Louisville School of Medicine,
Louisville, Kentucky 40292
v
vi CONTRIBUTORS
Pelayo Correa Department of Pathology, Louisiana State University Medical
Center, New Orleans, Louisiana 70112
Lydia Cox Department of Environmental Medicine, New York University
Medical Center, New York, New York 10016
Diane C. Currie Department of Environmental Medicine, New York Univer-
sity Medical Center, New York, New York 10016
David T. Denhardt Department of Biological Sciences, Rutgers University,
Piscataway, New Jersey 08855
Thomas H. Finlay Department of Obstetrics and Gynecology, New York
University Medical Center, New York, New York 10016
Peter Flecker Institute for Physiological Chemistry, University of Mainz,
W-6500 Mainz, Germany
Elizabeth Fontham Department of Pathology, Louisiana State University
Medical Center, New Orleans, Louisiana 70112
Krystyna Frenkel Departments of Environmental Medicine and Pathology,
New York University Medical Center, New York, New York 10016
Mendel Friedman Western Regional Research Center, Agricultural Research
Service, U.S. Department of Agriculture, Albany, California 94710
Seymour J. Garte Department of Environmental Medicine, New York Uni-
versity Medical Center, New York, New York 10016
Susan S. Kadner Department of Obstetrics and Gynecology, New York Uni-
versity Medical Center, New York, New York 10016
Joseph Katz Department of Obstetrics and Gynecology, New York Univer-
sity Medical Center, New York, New York 10016
Ann R. Kennedy Department of Radiation Oncology, School of Medicine,
University of Pennsylvania, Philadelphia, Pennsylvania 19104
Mortimer Levitz Department of Obstetrics and Gynecology, New York Uni-
versity Medical Center, New York, New York 10016
Daniel S. Longnecker Department of Pathology, Dartmouth Medical School,
Hanover, New Hampshire 03755
Joan Motz Department of Environmental Medicine, New York University
Medical Center, New York, New York 10016
Joseph Nickels, Jr. Department of Microbiology and Molecular Genetics,
Rutgers University, New Brunswick, New Jersey 08903
CONTRIBUTORS vii
Uma Raju Department of Obstetrics and Gynecology, New York University
Medical Center, New York, New York 10016
George Ritchie Department of Physics, Rider College, Lawrenceville, New
Jersey 08648
B. D. Roebuck Department of Pharmacology and Toxicology, Dartmouth
Medical School, Hanover, New Hampshire 03755
Lorraine T. Schepis Department of Molecular Biology, Princeton University,
Princeton, New Jersey 08530
Tomio Takeuchi Institute of Microbial Chemistry, Shinagawa-ku, Tokyo 141,
Japan
Snait Tamir Department of Obstetrics and Gynecology, New York University
Medical Center, New York, New York 10016
Wataru Tanaka Institute of Microbial Chemistry, Shinagawa-ku, Tokyo 141,
Japan
Walter Troll Department of Environmental Medicine, New York University
Medical Center, New York, New York 10016
Kazuo Umezawa Department of Applied Chemistry, Faculty of Science and
Technology, Keio University, Kohoku-ku, Yokohama 223, Japan
Jonathan Yavelow Department of Biology, Rider College, Lawrenceville,
New Jersey 08648
Preface
Protease inhibitors (PIs) are widely distributed in plants and animals, and have a
variety of functions, which include preventing digestion of seeds by insects and
modifying blood clotting in animals. After it was noted that synthetic and natural
inhibitors suppress two-stage carcinogenesis and breast cancer, extensive work
investigating PIs as chemopreventive agents was started.
PIs are unique in that they interfere with cancer development in a variety of
ways, including suppression of oxygen radicals, oncogenes, and metastases.
Epidemiologic evidence supports their prevention of major human cancers in
populations that consume foods containing them. Their supervised use in humans
is on the threshold of development.
The epidemiologic discovery of the importance of lentils and other seeds
rich in PIs in preventing many human cancers allowed us to look at the action of
PIs as chemopreventive agents, as reviewed in Chapter I (Fontham and Correa).
Chapter 2 (Kennedy) discusses the role of natural PIs (e.g., the Bowman-Birk
inhibitor) as anticarcinogens and the possible limitations of their use. In Chapter
3 (Kennedy), the transformation of C3HI lOTlh cells caused by carcinogens and
promoters is shown to be suppressed by PIs. Bowman (Chapter 4) relates the
discovery of inhibitors in soybeans that are distinct from the Kunitz inhibitor, and
the occurrence of a similar inhibitor in peanuts and other legumes. Chapter 5
(Birk) is an overview of PIs of plant origin and their role in human nutrition. In
Chapter 6, Brandon and colleagues report on the measurement of soybean trypsin
inhibitors by monoclonal antibodies, their possible use for cellular delivery, and
the effect of food processing on the survival of the inhibitors. Chapter 7 (Um
ezawa et at.) concerns low-molecular-weight inhibitors, isolated from strep
tomycetes, that have been shown to suppress cancer in animal and some human
experiments and are also useful for in vitro and oncogene expression studies. PI
synthesis by MCF-7 breast cancer cell lines is discussed in Chapter 8 (Finlay et
al.). ai-Trypsin and chymotrypsin inhibitors synthesized by breast cancers may
inhibit metastasis. In Chapter 9, Flecker analyzes the structure-activity relation-
ix
x PREFACE
ships of the Bowman-Birk inhibitor of serine proteinases, with a view toward
the design of new cancer chemopreventive agents. Troll (Chapter 10) discusses
the prevention of cancer by vitamin B3 compounds, PIs that are available for
human use. Billings (Chapter 11) details approaches to studying the target en
zymes of anticarcinogenic PIs. In Chapter 12, Colella and colleagues document
the anticarcinogenic activities of naturally occurring cysteine proteinase inhibi
tors. These PIs prevent metastasis of tumors and are distinct from serine PIs.
Yavelow and colleagues (Chapter 13) identify a chymotrypsin cell membrane
enzyme that acts as a possible receptor for chymotrypsin inhibitors. Frenkel
(Chapter 14) describes the role of reactive oxygen species in biological damage
and the effect of some chemopreventive agents. Chapters 15 (Garte et al.) and 16
(Chang and Kennedy) discuss PI suppression of the actions induced by the ras
and c-myc oncogene, respectively. Chapter 17 (Levitz et al. ) reviews the role of
esterases in steroid hormone turnover. Esterases in breast cyst fluid hydrolyze
steroid esters, modifying their action. The action of PIs in inducing pancreatic
cancer in animal models is reviewed by Roebuck and Longnecker (Chapter 18).
Contents
Chapter 1
The Epidemiologic Approach to the Study of Protease Inhibitors
Elizabeth Fontham and Pelayo Correa
1. Introduction ............................................. .
2. Descriptive Epidemiology .................................. 1
3. Analytical Epidemiology ................................... 2
4. Tools Needed for Epidemiologic Studies ...................... 4
5. Intervention Studies ....................................... 5
6. Cancer Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
7. Epilogue ................................................ 6
8. References............................................... 7
Chapter 2
Anticarcinogenic Activity of Protease Inhibitors: Overview 9
Ann R. Kennedy
1. Review of Data Showing Anticarcinogenic Activity of Protease
Inhibitors ................................................ 9
2. Potential Adverse Effects of Anticarcinogenic
Protease Inhibitors ........................................ 15
2.1. Effects of Protease Inhibitors on Growth .................. 15
2.2. Effects of Protease Inhibitors on the Pancreas· . . . . . . . . . . . . . . 16
2.3. Potential Effects of Protease Inhibitors on the
Immune System ...................................... 22
3. The Soybean-Derived BBI as an Anticarcinogenic Agent. . . . . . . . . 23
3.1. Review of Data on the Anticarcinogenic Activity of BBI . . . . . 23
xi
xii CONTENTS
3.2. Limitations of BBI as a Human Cancer Chemopreventive
Agent............................................... 44
4. Mechanism of Action of the Anticarcinogenic
Protease Inhibitors ........................................ 50
5. Summary ................................................ 54
6. References ............................................... 55
Chapter 3
In Vitro Studies of Anticarcinogenic Protease Inhibitors. . . . . . . . . . . . . 65
Ann R. Kennedy
1. Introduction .............................................. 65
2. Mechanism of Action of the Anticarcinogenic Protease Inhibitors in
the Suppression of Transformation in Vitro .................... 80
3. References ............................................... 86
Chapter 4
Discovery and Background of the Bowman-Birk
Protease Inhibitors ........................................... 93
Donald E. Bowman
1. Origin of Interest in Legumes ............................... 93
2. Unexpected Protease Inhibition by Amylase
Inhibition Preparations ..................................... 93
3. References............................................... 95
Chapter 5
Protease Inhibitors of Plant Origin and Role of Protease Inhibitors in
Human Nutrition: Overview ................................... 97
Yehudith Birk
1. Introduction 97
2. Protease Inhibitors from Legume Seeds ...................... . 98
2.1. STI ................................................ . 98
2.2. BBI ............................................... . 98
3. Protease Inhibitors from Other Plant Sources .................. . 101
3.1. Potato Protease Inhibitors ............................. . 101
3.2. Squash Protease Inhibitors ............................. . 101
3.3. Protease Inhibitors in Cereals .......................... . 101
4. Role in Nutrition ......................................... . 102
4.1. Effect on Growth .................................... . 102
4.2. Effects on the Pancreas ............................... . 102