Table Of ContentBiochemistry of
Human Cancer
Oscar Bodansky, M.D., Ph.D.
Member Emeritus, Sloan-Kettering Institute for Cancer Research
Emeritus, Memorial Hospital for Cancer and Allied Diseases
Formerly, Chairman, Department of Biochemistry
Memorial Hospital for Cancer and Allied Diseases
Guest Investigator, The Rockefeller University
New York, New York
ACADEMIC PRESS New York San Francisco London 1975
A Subsidiary of Harcourt Brace Jovanovich, Publishers
COPYRIGHT © 1975, BY ACADEMIC PRESS, INC.
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Library of Congress Cataloging in Publication Data
Bodansky, Oscar, Date
Biochemistry of human cancer.
Includes bibliographies and index.
1. Cancer. 2. Metabolism, Disorders of.
I. Title. [DNLM: 1. Neoplasms. QZ200 B666b
RC269.B55 616.9'94'071 74-10220
ISBN 0-12-109850-8
PRINTED IN THE UNITED STATES OF AMERICA
To
Barbara Biber Bodansky
and
Margery B. Franklin
Preface
Biochemistry emerged as a well-defined discipline during the last
quarter of the nineteenth century. Its application to the study of human
cancer was begun almost simultaneously. In 1885 Freund published his
studies on hyperglycemia and in 1889 Müller described his investigations
on nitrogen balance. The pace of biochemical investigations in human
cancer has accelerated rapidly since then, and in the past twenty-five
years particularly a most intensive effort has been made in this direction.
The purpose of this book is to describe and evaluate the present status
of these biochemical studies in human cancer and the knowledge we
have gained. Biochemical studies of cancer at molecular, cellular, and
animal levels have been considered in a number of monographs. Refer-
ence to these investigations in this book are brief, and are presented
as the background for human studies. Early investigations in various
fields of human cancer are frequently noted, not only as an acknowledg-
ment to those who initiated the work but also as a guide to those who
may wish to engage in similar studies. In this, as in other areas, one
cannot fail to be aware of Santayana's statement that "he who does not
remember the past is condemned to repeat it."
It was felt that this book would be most useful if the material
xii
xiii
PREFACE
were arranged generally according to the organ site of the neoplasms
rather than under general biochemical categories. However, to avoid
repetition, certain features of human cancer such as general metabolic
characteristics, enzymic aspects, and immunochemical considerations
have been described in the first five chapters. Although separate chapters
on pulmonary and prostatic neoplasms are not presented, the important
biochemical aspects of these neoplasms such as those characterizing
carcinoid and ectopic pulmonary neoplasms and the serum acid and
alkaline phosphatase activities of prostatic carcinoma have been described
in other chapters. A monograph on the "Biochemistry of Brain Tumors" has
recently been written by M. Wolleman (University Park Press, Baltimore,
Maryland, 1974). The normal human biochemistry of the various organs
in which the major types of neoplasms occur has usually been presented,
to the extent deemed relevant, as introductory portions to the chapters
or occasionally has been interwoven with the discussion of the various
types of neoplasms resident in the organ. Where it was considered useful,
brief case reports from the literature have been presented to illustrate
correlations between biochemical and clinical findings.
We have attempted to indicate the clinical importance of various types
of neoplasms by noting the incidence and mortality rates at the beginning
of each chapter dealing with a particular group of neoplasms. It has not
always been possible to apportion space according to such clinical
importance, for many of the common tumors have received relatively
little biochemical or, for that matter, other basic science study, whereas
some groups of rare and esoteric neoplasms have been the subject
of much successful biochemical investigation.
The author has avoided an encyclopedic presentation of his material
for obviously such an approach would have increased the size of this
volume substantially. Accordingly, references to original work are illus-
trative rather than comprehensive, and the author feels an apology is due
to the investigators both in this country and abroad whose studies it was
not possible to cite because of limitation of space.
In reproducing various illustrations and tabular data, the author has
indicated the source of the material in the appropriate places throughout
the book. He wishes to take this opportunity to express his gratitude
to authors and publishers of various journals and monographs for granting
permission to reproduce such material.
It is also a great pleasure to acknowledge the assistance of Susan
London who, throughout a period of three years, has industriously and
faithfully typed the drafts of the manuscript and helped to verify
references.
The author is indebted to his many clinical and research colleagues and
xiv
PREFACE
friends at Memorial Hospital and Sloan-Kettering Institute who, in
formal presentations as well as in informal luncheon discussions and
corridor conversations during a period of over twenty-five years, helped
to supply a background for the contents of this book. In particular,
he wishes to thank Dr. Martin Lipkin, Dr. W. P. Laird Myers, and
Dr. Robert D. Leeper, who have been kind enough to read Chapters 8,
10, and 13, respectively, of the final manuscript and to offer helpful
comments. The author will at all times welcome suggestions from the
readers of this book.
Oscar Bodansky
1
General Metabolie
Characteristics in Cancer
I. Introduction
For many years, the concept has recurred that human cancer, regard-
less of its particular site or pathological nature, is characterized by
certain general metabolic features. These have included the existence
of anorexia and cachexia, a greater than normal intake of protein to
maintain nitrogen equilibrium, the depletion of body fat, disturbances
in carbohydrate metabolism, and changes in the protein and lipid patterns
of blood serum. At various times, and as an ancillary to these concepts,
the idea has also arisen that it is possible to devise a general diagnostic
blood test for human cancer, again regardless of its particular type or
site. The present chapter will review and assess the evidence for these
general beliefs.
II. Protein Metabolism
A. Introduction
The various aspects of normal protein metabolism such as the digestion
of protein, absorption of amino acids, the biosynthesis of amino acids
and peptides, and the biosynthesis of protein constitute a vast and impor-
1
2 1. GENERAL METABOLIC CHARACTERISTICS IN CANCER
tant area which is discussed in detail in various biochemistry texts and
to which the reader of this volume is referred. Questions naturally arise
concerning the extent to which these mechanisms apply in tumor cells
or in tumor-bearing animals, and whether there are any discernible differ-
ences between the modes of protein biosynthesis in normal and tumor-
bearing animals.
Protein biosynthesis has been studied in such tumor cell systems as
mouse ascites tumor cells (Littlefield and Keller, 1957), L-1210 mouse
ascites leukemia cells (Ochoa and Weinstein, 1964), and the Novikoff
rat ascites tumor (Griffin et ah, 1965). Protein biosynthesis in tumor
has been compared with that in microbial and normal mammalian sys-
tems, particularly with respect to (a) specificity of aminoacyl transfer
ribonucleic acid and transfer enzymes, (b) aminoacyl transfer ribo-
nucleic acid ribosomal system, (c) the ribosomal polysomal complex,
and (d) the coding characteristics. In a review of such studies, Griffin
(1967) noted that there appeared to be no evidence for any differences
in the mechanism of protein biosynthesis between normal and cancer
cells. However, there may be some tumors as, for example, multiple my-
eloma, in which specific γ-globulins are synthesized to an excessive extent
(Chapter 5).
β. Overall Protein and Nitrogen Metabolism
1. Introduction
The food nitrogen which is ingested by the human organism consists
mostly of protein, but to some extent also some of the metabolic products
such as purines or amino acids which are found in the particular plant
or animal substance that is eaten. The pepsin of the stomach, derived
from its zymogen precursor, pepsinogen, and the trypsin and chymotryp-
sin convertible from their precursors in the pancreatic secretions break
down the large protein molecules to polypeptides and free amino acids.
Complete digestion to amino acids is accomplished by the action of
carboxypeptidase from the pancreas and the amino-, tri-, and di-pep-
tidases of the intestinal secretions. Normally, about 95% of food protein
is digested, so that the feces contain only about 5% protein, chiefly keratin,
which remains undigested.
2. Fate of Amino Acids
The amino acids and other small nitrogen-containing molecules which
thus arise by digestion of the food are absorbed into the bloodstream
II. PROTEIN METABOLISM 3
and pass into the various tissues. There, they mix with the corresponding
molecules to form the various metabolic pools which are in ceaseless,
dynamic equilibrium with each other. Whether derived from the diet
or from endogenous sources, amino acids may be channeled into one
or more of the following metabolic pathways: (a) incorporation into
peptides and proteins, (b) utilization of the nitrogen and/or carbon
for the synthesis of different amino acids, (c) utilization for synthesis of
nitrogenous compounds which are not amino acids, and (d) removal
of the «-amino group by transamination or oxidation with the subsequent
formation of ammonia which may itself follow any of several paths.
Some of it recycles into the metabolic stream by entering into the
synthesis of glutamic acid, glutamine, and carbamyl phosphate. Part
of it is excreted as such, constituting about 5-6% of the total nitrogen
in the urine of the normal person but changing in response to alterations
in the acid-base balance of the individual. However, most of the ammonia
is converted to urea, constituting about 90% of the total nitrogen excreted
by man in the urine. The formation of urea occurs by the entrance
of NH into a cycle of reactions. Under the influence of carbamyl phos-
3
phate synthetase in the liver, NH interacts with C0 and ATP to form
3 2
carbamyl phosphate. Ornithine transcarbamylase then catalyzes the inter-
action of carbamyl phosphate with ornithine to form citrulline and inor-
ganic phosphate. In the next reaction, catalyzed by arginosuccinic acid
synthetase in the presence of ATP and Mg2+, citrulline interacts with
aspartic acid to form arginosuccinic acid, AMP, and pyrophosphate.
Arginosuccinase cleaves arginosuccinic to form arginine and fumaric
acid. Finally, arginase catalyzes the hydrolysis of arginine to form urea
and ornithine, and the latter compound is then recycled again.
3. Relationship between Nitrogen Intake
and Excretion
Much of our information on the intermediary metabolism of protein
has been gained from studies of lower organisms such as bacteria and
yeasts and of smaller animals such as mice and rats. Obviously, inter-
mediary metabolism, either in normal man or in the patient with cancer,
is much less accessible to study, and much of our available knowledge
concerns the overall metabolism of proteins. San Pietro and Rittenberg
(1953) formulated the kinetic interrelationships in human protein metab-
olism. Using equations developed from assumptions for the nitrogen
content of the body, the urea pool, the intake and excretion of nitrogen,
and analyzing the urine for total nitrogen and 15N concentrations of
ammonia, urea and total nitrogen following the intravenous injection
4 1. GENERAL METABOLIC CHARACTERISTICS IN CANCER
of 15N-labeled glycine, they obtained values for protein synthesis of
0.58 gm/kg body weight per day for one individual and 0.86 and 1.28
per kg body weight per day for a second individual on two different
occasions.
In 1920, Sherman summarized the results of 109 nitrogen balance
studies that had been conducted on humans since the early studies of
Hirschfeld (1887). In many of these studies and, indeed, in Hirschfeld's
own study, only the urinary nitrogen was determined and assumed to
represent the total excretion of nitrogen. The protein requirement or
the point at which the nitrogen intake in protein was equivalent to
the nitrogen excretion was, on the average, 0.64 gm protein or 102 mg
nitrogen per kg of body weight. Sherman's own balance study (1920)
on one individual included the fecal nitrogen, and yielded a requirement
of 74 mg nitrogen per kg of body weight.
Since these early reports, more elaborate studies have determined
balances at varying protein intakes. Regression equations have been
developed which connect (a) nitrogen balances as ordinates versus nitro-
gen intake as abscissae, both expressed as gm per day per m2 of body
surface (Hegsted et ah, 1946); (b) nitrogen intake as ordinates versus
nitrogen balance as abscissae, both in mg per day per basal calorie
(Bricker et ah, 1945); (c) nitrogen balance as ordinates versus nitrogen
as intake, both in mg per day per kg of body weight (Beattie et ah,
1948); and (d) nitrogen excretion as ordinates versus nitrogen intake
as abscissae, both as mg per day per kg of body weight (Schwartz
et ah, 1956). Obviously, where the nitrogen balances are ordinates, the
value of the abscissae at y = 0 represents the intake, x, necessary to
keep the subject in balance. Where the values for nitrogen excretion
are on the ordinates, and those for nitrogen intake are the abscissae,
the point at which x is equal to y also yields the intake necessary for
balance. Calculations from equations based on studies of well-fed persons
have yielded values of 67-74 mg/kg/day as the amount of nitrogen neces-
sary for balance (Bricker et ah, 1945; Hegsted et ah, 1946). Calculations
from the equations formulated from the data of von Hoesslin (1919)
and of Beattie et ah (1948) on subjects recovering from severe malnutri-
tion yielded a value of 112 mg nitrogen per kg per day (Schwartz
et ah, 1956).
The daily intakes necessary to obtain zero balance vary with the type
of protein in the diet. Thus, from the data of Bricker et ah (1945),
it may be calculated that, on a milk diet, a protein intake of 58 mg
nitrogen per kg per day would suffice, whereas, on a white flour intake,
103 mg nitrogen per kg per day would be necessary. These differences
depend to some degree on the digestibility of the protein and, hence,
