Table Of ContentThis is a volume in
CELL BIOLOGY
A series of monographs
Editors: D. E. Buetow, I. L. Cameron, G. M. Padilla, and A. M. Zimmerman
A complete list of the books in this series appears at the end of the volume.
NOVEL
APPROACHES
TO CANCER
CHEMOTHERAPY
Edited by
Prasad S. Sunkara
Merrell Dow Research Institute
Cincinnati, Ohio
ACADEMIC PRESS, INC.
(Harcourt Brace Jovanovich, Publishers)
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Toronto Montreal Sydney Tokyo
COPYRIGHT © 1984, BY ACADEMIC PRESS, INC.
ALL RIGHTS RESERVED.
NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR
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ACADEMIC PRESS, INC.
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United Kingdom Edition published by
ACADEMIC PRESS, INC. (LONDON) LTD.
24/28 Oval Road, London NW1 7DX
Library of Congress Cataloging in Publication Data
Main entry under title:
Novel approaches to cancer chemotherapy.
Includes index.
1. Cancer—Chemotherapy. I. Sunkara, Prasad S.
[DNLM: 1. Antineoplastic Agents--therapeutic use.
2. Neoplasms—drug therapy. QZ 267 N937]
RC271.C5N68 1984 616.99*4061 84-9292
ISBN 0-12-676980-X (alk. paper)
PRINTED IN THE UNITED STATES OF AMERICA
84 85 86 87 9 8 7 6 5 4 3 2 1
Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Samuel Baron (1), Department of Microbiology, The University of Texas Medical
Branch at Galveston, Gal veston, Texas 77550
Peter Buglelski (165), Smith Kline & French Laboratories, Philadelphia, Pennsylvania
19101
Ivan L. Cameron (355), Department of Cellular and Structural Biology, The University
of Texas Health Science Center at San Antonio, San Antonio, Texas 78284
Frances M. Davis (23), Department of Chemotherapy Research, M. D. Anderson Hos
pital and Tumor Institute, The University of Texas System Cancer Center, Houston,
Texas 77030
Isaiah J. Fidler1 (231), Cancer Metastasis and Treatment Laboratory, Litton Biomedics,
Inc.—Basic Research Program, Frederick Cancer Research Facility, National Cancer
Institute, Frederick, Maryland 21701
W. Robert Fleischmann, Jr. (1), Department of Microbiology, The University of Texas
Medical Branch at Galveston, Galveston, Texas 77550
Susan J. Friedman (329), Department of Pharmacology, and Oncology Research Group,
Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
Kenneth V. Honn (127), Department of Radiology and Department of Radiation Oncol
ogy, Wayne State University, Detroit, Michigan 48202
J. O'Neal Johnston (307), Merrell Dow Research Institute, Cincinnati, Ohio 45215
Richard Kirsch (165), Smith Kline & French Laboratories, Philadelphia, Pennsylvania
19101
Present address: Department of Cell Biology, M.D. Anderson Hospital and Tumor
Institute, The University of Texas System Cancer Center, Houston, Texas 77030.
xi
xii Contributors
Eugenie S. Kleinerman2 (231), Laboratory of Molecular Immunoregulation, Biological
Response Modifiers Program, Frederick Cancer Research Facility, National Cancer
Institute, Frederick, Maryland 21701
Gary R. Klimpei (1), Department of Microbiology, The University of Texas Medical
Branch at Gal veston, Gai veston, Texas 77550
Lawrence J. Marnett (127), Department of Chemistry, Wayne State University, Detroit,
Michigan 48202
Brian W. Metcalf3 (307), Merrell Dow Research Institute, Cincinnati, Ohio 45215
Kenji Nishioka (251), Department of General Surgery/Surgical Research Laboratory
and Department of Biochemistry, M.D. Anderson Hospital and Tumor Institute, The
University of Texas System Cancer Center, Houston, Texas 77030
George M. Padilla (269), Department of Physiology, Duke University Medical Center,
Durham, North Carolina 27710
Vladimir Petrow (269), Department of Pharmacology, Duke University Medical Center,
Durham, North Carolina 27710
George Poste (165), Smith Kline & French Laboratories, Philadelphia, Pennsylvania,
and Department of Pathology and Laboratory Medicine, University of Pennsylvania
School of Medicine, Philadelphia, Pennsylvania
Nellikunja J. Prakash (93), Merrell Dow Research Institute, Cincinnati, Ohio 45215
Potu N. Rao (23), Department of Chemotherapy Research, M.D. Anderson Hospital and
Tumor Institute, The University of Texas System Cancer Center, Houston, Texas
77030
Philip Skehan (329), Department of Pharmacology, and Oncology Research Group,
Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
Prasad S. Sunkara (93), Department of Chemotherapeutics, Merrell Dow Research
Institute, Cincinnati, Ohio 45215
Stephen K. Tyring (1), Department of Microbiology, The University of Texas Medical
Branch at Gal veston, Gai veston, Texas 77550
William R. Voss (1), Department of Microbiology, The University of Texas Medical
Branch at Gal veston, Gai veston, Texas 77550
2Present address: Department of Cell Biology, M.D. Anderson Hospital and Tumor
Institute, the University of Texas System Cancer Center, Houston, Texas 77030.
3Present address: Smith Kline & French Laboratories, Philadelphia, Pennsylvania
19101.
Preface
The major aim of this book is to collate in one source new and emerging
theories in tumor biology and to discuss their potential usefulness in developing
new therapeutic approaches to cancer therapy. It is clear that a selective therapeu
tic attack on cancer cells is possible only when the basic differences between
cancer and normal cells are well understood. In recent years a number of bio
logical and biochemical differences have been discovered. This monograph
illustrates how interaction among researchers in different areas of biology, im
munology, and biochemistry can help develop selective therapeutic agents
against cancer.
Each chapter stresses a unique property of a cancer cell and describes in detail
how a novel therapeutic approach can be developed. Chapters 1, 2, 5, 6, and 7
deal with new emerging areas of cancer therapy such as the use of interferon,
monoclonal antibodies, liposomes, lymphokines, and immunomodulators (tuft-
sin), respectively. The other six chapters deal with some of the newly identified
biochemical and enzyme targets in cancer cells such as polyamines (Chapter 3),
prostaglandin, thromboxane, and leukotrienes (Chapter 4), 5a-reductase (Chap
ter 8), aromatase (Chapter 9), cell membrane glycoproteins (Chapter 10), and
sodium flux (Chapter 11). These chapters dealing with the biochemical
approaches include recent developments which should provide the reader with
new and rational approaches to cancer therapy.
xiii
xiv Preface
I hope this book will stimulate biologists, biochemists, immunologists, and
molecular biologists to interact with one another to exploit the unique properties
of cancer cells in order to develop new approaches to cancer therapy.
I am extremely grateful to Anne C. Hagan for her assistance in editing the
volume. My special thanks go to the contributing authors for their enthusiasm
and willingness to write about their work.
Prasad S. Sunkara
Interferon and Cancer: Current Use and
Novel Approaches
W. ROBERT FLEISCHMANN, JR., GARY R.
KLIMPEL, STEPHEN K. TYRING, WILLIAM R.
VOSS, AND SAMUEL BARON
Department of Microbiology
The University of Texas Medical Branch at Galveston
Galveston, Texas
I. Introduction 1
II. Interferon Clinical Trials 5
III. Combination Therapies 6
IV. A Murine B Melanoma Model for Assessment of Therapy of
16
Lymph Node Métastases 10
V. Potential for Direct Cytolysis of Tumor Cells by Interferon 12
VI. Activation of NK Cells 14
VII. Interferon and Hematopoiesis 15
VIII. Conclusions 16
References 16
I. INTRODUCTION
Interferons (IFN's) have been attracting considerable attention for their anti-
tumor properties. However, they are named and classified on the basis of their
antiviral properties. They are defined as proteins that exert ''virus nonspecific,
antiviral activity at least in homologous cells through cellular metabolic pro
cesses involving synthesis of both RNA and protein" (Stewart et al., 1980).
Three antigenically distinct types of interferon are recognized (Baron et al,
1
Novel Approaches to Cancer Chemotherapy
Copyright © 1984 by Academic Press, Inc.
All rights of reproduction in any form reserved.
ISBN 0-12-676980-X
2 W. Robert Fleischmann, Jr. et al.
1982). IFN-α is produced by B cells, null cells, and macrophages upon exposure
to B-cell mitogens, viruses, foreign cells, or tumor cells. IFN-ß is produced by
fibroblasts upon exposure to viruses or foreign nucleic acids. IFN-7 is produced
by T cells and perhaps by null cells stimulated with T-cell mitogens, specific
antigens, or interleukin 2 (IL 2).
All three interferon types exhibit antitumor and immunoregulatory properties
in addition to their antiviral properties. They do, however, differ in their relative
activities. For example, IFN-7 induces the antiviral state more slowly than either
IFN-a or IFN-ß (Dianzani et al., 1978). Also, IFN-7 has been shown in labora
tory studies to have more potent immunosuppressive (Sonnenfeld et al., 1977)
and antitumor activities than either IFN-a or INF-ß (Salvin et al., 1975; Crane et
al, 1978; Blalock et al., 1980; Fleischmann, 1982) (see later). This high poten
cy of IFN-7 antitumor activity observed in model systems raises the prospect that
the use of IFN-7 in the clinic may greatly increase the effectiveness of interferon
therapy.
A considerable amount of study has been directed toward understanding the
mechanisms by which the interferon system functions. Figure 1 depicts a work
ing model for the induction and antiviral action of interferon. In this model,
interferon is induced by an event occurring during viral replication. The cellular
Inducers Producing Cell
Fig. 1. Cellular events of the induction, production, and action of interferon (IFN). Inducers of
IFN react with cells to derepress the IFN gene(s) (A). This leads to the production of mRNA for IFN
(B). The mRNA is translated into the IFN protein (C) that is secreted into the extracellular fluid (D),
where it reacts with the membrane receptors of cells (E). The IFN-stimulated cells derepress genes
(F) for effector proteins (AVP) that establish antiviral resistance and other cell changes. The activated
cells also stimulate contacted cells (G) by a still unknown mechanism to produce AVP. (Reproduced
with permission from Baron et al., Texas Reports on Biology and Medicine 41, 1-12, 1982.)
1. Interferon and Cancer 3
^— INTERFERON
MACROPHAGE
SENSITIZED
TCELL
INCREASED^
CYTOTOXICITY\ „
INCREASED
CYTOTOXICITY
DIRECT ANTICELLULAR
EFFECT
TUMOR CELL
Fig. 2. Antitumor activity of interferon. Interferon has both direct and indirect effects on tumor
cells. Interferon has direct anticellular effects by blocking tumor cell growth and, in some cases,
causing direct cytolysis of the tumor cells. Interferon's indirect effects are mediated by cytotoxic
effector cells such as macrophages, natural killer (NK) cells, and sensitized T cells.
genome is derepressed to produce a specific mRNA, which is then translated to
produce interferon. The interferon is released into the surrounding fluid by the
producing cell, where it can now interact with specific receptors on the surface of
responding cells to initiate a series of events, involving synthesis of both mRNAs
and proteins, which lead to the establishment of the antiviral state. The figure
also details another interesting feature of interferon action. The interferon re
sponding cell may transfer a signal to a neighboring cell, which causes the
neighboring cell to develop an antiviral state without directly interacting with
interferon.
The antitumor action of interferon is more complex than the antiviral action.
The model just given may serve as a general model for the direct anticellular
action of interferon, even to the transfer of antitumor activity from a responding
cell to a neighboring cell (Lloyd et al., 1983). However, in addition to its direct
effect on the tumor cell, interferon acts on tumor cells indirectly through its
activation of the host's cell-mediated immunity system (Fig. 2). Thus, interferon
activates and enhances the antitumor activity of natural killer (NK) cells (Trin-
chieri et al., 1978; Gidlund et al., 1978; Svet-Moldavsky and Chernyakhov-
skaya, 1967; Djeu et al., 1979) and macrophages (Chapes and Tompkins, 1979;
Stanwick et al., 1980; Schultz, 1980). Unfortunately, interferon also protects
tumor cells from the cytolytic action of these cells (Trinchieri et al., 1981). It is
the sum of these positive and negative, direct and indirect interferon actions that
constitutes the antitumor activity of interferon. An understanding of these in
teractions should enable us to maximize the antitumor activity of interferon and
to exploit its potential fully.
