Cancer Biology and Therapeutics

266 Pages·1987·28.949 MB·English

by  George Weber (auth.), Joseph G. Cory, Andor Szentivanyi (eds.)

Cancer Biology
and Therapeutics
Cancer Biology
and Therapeutics
Edited by
Joseph G. Cory
and
Andor Szentivanyi
University of South Florida
Tampa, Florida
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Cataloging in Publication Data
H. Lee Moffitt International Symposium on Cancer Biology and Therapeutics (1st:
1986: Tampa, Fla.)
Cancer biology and therapeutics.
"Proceedings of the First Annual H. Lee Moffitt International Symposium on Cancer
Biology and Therapeutics, held January 20-22, in Tampa, Florida"-T.p. verso.
Includes bibliographies and index.
1. Cancer-Chemotherapy-Congresses. 2. Cancer-Congresses. 3. Antineoplastic
agents-Congresses. I. Cory, Joseph G. II. Szentivanyi, Andor. 111. Title. [DNLM: 1.
Medical Oncology-congresses. 2. Neoplasms-drug therapy-congresses. W3 H105
Ist 1986c/QZ 267 Hll 1986c]
RC271.C5H3 1986 616.99'4061 86-30574
ISBN 978-1-4757-9566-0 ISBN 978-1-4757-9564-6 (eBook)
DOI 10.1007/978-1-4757-9564-6
Proceedings of the First Annual H. Lee Moffitt International Symposium
on Cancer Biology and Therapeutics, held January 20-22, 1986,
in Tampa, Florida
© 1987 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1987
Softcover reprint of the hardcover 1st edition 1987
All 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
FOREWORD
In anticipation of the opening of the H. Lee Moffitt Cancer Center and
Research lnstitut~ on the campus of the University of South Florida, an
international symposium, "The First Annual H. Lee Moffitt Symposium on Cancer
Biology and Therapeutics" was held in Tampa, Florida on January 20-22, 1986.
In this first symposium we decided to present a broad-based series of topics
dealing with the major issues in the field of cancer. These topics ranged
from the biochemistry of the cancer cell to the design of antineoplastic
agents, through tumor cell heterogeneity, treatment of ltuman neoplasms to
immunological aspects of cancer biology and tr~atment. The speakers chosen
represented individuals of international acclaim who are very active in the
area of cancer research and treatment. The symposium brought together scien
tists/physicians from six nations including Austria, Canada, France, Hungary,
West Germany, and of course, the United States. The congeniality of the
participants promoted the friendly exchange of knowledge which, it is hoped,
will greatly hasten the time when successful management of human cancer
will become routine.
Future symposia in this series will be highly focused and will deal
with a single facet of this vast field of cancer research and treatment.
Joseph G. Cory, Editor
Andor Szentivanyi, Editor
University of South Florida, 1986
V
ACKNOWLEDGMENTS
This volume presents the Proceedings of the H. Lee Moffitt International
Syn~osium on Cancer Biology and Therapeutics which was held in Tampa, Florida
on January 20, 21, and 22, 1986. This Symposium was funded through the
City of Tampa's International Trade Fair Advisory Board and this assistance
is gratefully acknowledged. Mr. John Sellers, Director of the Convention
Facilities was very helpful and encouraging in the planning and running of
the Symposium. The assistance of the H. Lee Moffitt Cancer Center and
Research Institute in this endeavor is very much appreciated.
This Symposium could not have been run as efficiently and smoothly as
it was without the dedicated efforts of Pierre J. Bouis, M.D., and Joan
Runnels of the Office of Continuing Medical Education of the University of
South Florida College of Medicine.
Last, but by no means least, the valuable assistance of Nancy W. Adams
in the development of the Symposium, and Ann H. Cory and Christine M. Abarca
in the preparation of this volume is most sincerely acknowledged and
appreciated.
Joseph G. Cory
Andor Szentivanyi
CONTENTS
SECTION I
BIOCHEMISTRY OF THE CANCER CELL AND SELECTIVITY OF DRUG ACTION
Biochemical Strategy of Cancer Cells and the Targeting of
Chemotherapy with Tiazofurin, Acivicin, and Dipyridamole 3
G. Weber
The Biological Bases for the Design of Anticancer Agents 23
J. A. Montgomery
Biochemistry of Methotrexate: Teaching an Old Drug New Tricks 43
F. M. Huennekens, T. H. Duffy, L. E. Pope, G. G. Grundler,
J. K. Sato, and K. S. Vitols
SECTION II
BIOLOGICAL AND CLINICAL IMPLICATIONS OF TUMOR CELL
HETEROGENEITY AND METASTASES
Biological and Clinical Implications of the Stem Cell
Concept in Human Malignancy • • • • • 65
R. N. Buick
Membrane Properties of Lewis Lung Tumor Cells with "Low" and
"High" Metastatic Capacity: Anti-metastatic Effect of
a Glycosaminoglycan Biosynthesis Blocking Agent
5-Hexyl-21-deoxyuridine (HUdR) •••••• 79
K. Lapis, J. Timar, K. Pal, A. Jeney, F. Timar, and
L. Kopper
Implications of Therapy-induced Genetic/Epigenetic
Modulations of Tumor Progression and Tumor Cell
Heterogeneity for the Treatment of Cancer 95
R. S. Kerbel, R. G. Liteplo, and P. Frost
SECTION III
APPROACHES TO THE TREATMENT AND DIAGNOSIS OF CANCER
Site-directed Cerobination Chemotherapy 107
Joseph G. Cory
ix
Sugar Analogs and 5-Fluorouridine in Combination Chemotherapy 119
D. Keppler, A. Holstege, and G. Weckhecker
New Strategies for the Improvement of Alkylating
Antitumor Agents • • • • • • • • • • • • • • 127
H. Grunicke, w. Doppler, J, Hofmann, H. Lindner,
K. Maly, H. Oberhuber, B. Puschendorf, and
H. Ringsdorf
Application of Proton Nuclear Magnetic Resonance to
Tumor Biology • • • • • • • • • • • • • 141
P. G. Braunschweiger and M. A. Rieb
SECTION IV
CLINICAL ADVANCES AND PROBLEMS IN THE TREATMENT OF HUMAN TUMORS
Relationships of Cell Biology to Therapy in
Childhood Leukemia • • • • • • 161
A. T. Look, D. L. Williams, and J, V. Sirnone
Clinical Cancer Treatment and Drug Resistance:
The Interface of the Clinic and the Labaratory 173
E. Reed and B. A. Chabner
SECTION V
INDUCTION, PREVENTION, AND MODULATION OF CANCER
Nitrosamines and Human Cancer: Some Implications of
Basic Research 183
P. N. Magee
Molecular Mechanisms in Protection Against Carcinogenesis 197
P. Talalay, M. J. De Long, and H. J. Prochaska
Antineoplastic Agents and Cancer Cell Differentiation 217
A. Bloch
SECTION VI
IMMUNOLOGICAL ASPECTS OF NEOPLASIA
A Reappraisal of Cytotoxic Lymphocytes in Human
Tumor Immunology • • • • • • • • • • • • 225
J, G. Sinkovics
From Tumor Relapse Prevention to Tumor
Induction Prevention • • • • • • 255
G. Mathe
Participants 271
Index • • • • • 273
X
SECTION I
BIOCHEMISTRY OF THE CANCER CELL AND SELECTIVITY OF DRUG ACTION
Biochemical Strategy of Cancer Cells and the Targeting of
Chemotherapy with Tiazofurin, Acivicin, and Dipyridamole
G. Weber
The Biological Bases for the Design of Anticancer Agents
J. A. Montgomery
Biochemistry of Methotrexate: Teaching an Old Drug New Tricks
F. M. Fuennekens, T. H. Duffy, L. E. Pope, G. G. Grundler,
J. K. Sato, and K. S. Vitols
BIOCHEMICAL STRATEGY OF CANCER CELLS AND TRE TARGETING OF CHEMOTHERAPY
WITH TIAZOFURIN, ACIVICIN, AND DIPYRIDAMOLE
George Weber
Labaratory for Experimental Oncology
Indiana University School of Medicine
Indianapolis, Indiana
INTRODUCTION
It is 25 years since I introduced the ideas of the molecular correla
tion concept as a theoretical and experimental method for discovering the
pattern of biochemical imbalance and its link with neoplastic transformation
and progression (1). This approachwas tested through application of the
concept of key enzymes in a particularly meaningful model system, the rat
hepatomas of different growth rates. The testing of the molecular correla
tion concept proved .that the biochemical strategy of the genome in neoplasia
can be identified by elucidating the pattern of gene expression as revealed
in the activity, amount, and isozymic program of the key enzymes. It was
shown that the activities of the key enzyrnes and metabolic pathways and the
concentrations of strategic nucleotides and amino acids are stringently
linked with neoplastic transformation and progression. Parameters that are
not stringently linked yield no pattern. The conclusion was drawn that
what is important about cancer is ordered; what is not, is the random element
and the diversity. This field was recently reviewed (2,3).
These investigations have done much to uncover the biochemical strategy
of cancer cells and the ordered pattern was identified in meaningful bio
chemical alterations in carbohydrate, purine, pyrimidine, cyclic nucleotide
and polyamine metabolism (3). Recent studies showed that the l!lolecular
correlation concept is also applicable to serine metabolism (4,5).
The molecular correlation concept provided a unifying approach in cancer
biochemistry and uncovered important aspects of the gene logic in cancer
cells. The indication was that in neoplastic cells a reprogramming of gene
expression took place which is manifested in the alterations in the concen
trations of key enzymes. The operation of reprogramming of gene expression
was demonstrated for seven key enzymes that are increased in activity in
glycolysis and the pentose phosphate pathway and in the biosynthesis of
purines and pyrimidines (3,6,7). Recently the first evidence was obtained
that a decrease in the activity of the rate-limiting enzyme of purine degra
dation, xanthine oxidase, was due to a decrease in enzyme amount (8). The
evidence for reprogramming of gene expression as manifested in changes in
the amounts of key enzymes is summarized in Table 1.
The general applicability of the molecular correlation concept received
much support, since it was shown to be valid for chemically- and virally-
3