Download Physical-Chemical Factors

Summary
ofthe
Informal
Discussion
Physical-Chemical
PREPARED
on
Factors
BY PAUL
K0TIN
National Cancer Institute, USPHS
Opening the session, DR. K0TIN remarked that those
who have been working in chemical carcinogenesis
are
experiencing the feeling that “we'vetrod this path before―
as they watch excitement grow about the viral etiology
of cancer.
Prior interest had been centered around the
appealing form of benzene rings and double bonds as struc
tural elements rather than helices, as at present.
He
recommended that those interested in carcinogenesis as a
response to viral agents or to other chemical agents recall
Dr. Francis' comment of the morning, which emphasized
that in carcinogenesis we are dealing neither with mutually
synthesis of what we choose to call the proximate car
cinogen.
The epidemiologist
should treat his human
population laboratory in much the same way as we do
the experimental laboratory, attempting to identify specific
preneoplastic sites as well as individuals at increased risk
to the development of cancer because of endogenous fac
tors or environmental
exposure.
Study of this group
offers the best hope for identifying and elucidating the
pathogenesis of a neoplasm prior to the appearance of the
overt lesion. Further, the role of transmissible
agents
exclusive
scribed can also be best investigated at this stage since the
agent, as is well known, need not be present in the induced
responses
at the
cellular
level
nor with
agents
which are mutually exclusive in all of their characteristics.
Dr. Miller's comprehensive
formal report adequately
attested both to the ubiquity and the long-time environ
mental presence of natural and synthetic carcinogens.
It
also emphasized the lack of structural uniformity among
the groups of carcinogens.
There is actually an absence of
specific structural requirements for chemical carcinogens.
Dr. Kotin again emphasized that there is an unuttered pre
amble to almost all sentences describing studies on chemi
cal carcinogenesis—namely,
that available data have been
obtained in the experimental laboratory. Evidence for the
carcinogenic potential of these compounds for man is at
best only inferential.
The differences among species, in
the carcinogenic effects of certain compounds discussed
by Dr. Miller, may in part be explained by the metabolic
differences among these species.
Dr. Miller's presentation raises several questions: “Why
and how do cells become cancerized?― Of equal moment
to this meeting is the question : “Whydo people, and only
certain ones at that, get cancer?― Why does the newborn
show increased sensitivity to carcinogenic agents?
Why
do the high or low cancer rates of their native countries
in the
pathogenesis
of any
of the
neoplastic
lesions
de
neoplasm.
Dr. Curtis was asked to clarify his thesis that chromo
somal or genetic lesions can be self-healing whether they
were inflicted by irradiation
or in the course of other
somatic mutations.
It was further questioned how one
can reconcile this theory with the idea that once chromo
somal material was lost it was gone forever.
On the basis
of his liver studies, Dr. Curtis appeared to question the
idea that the apparent progressive disappearance
of ab
normal
karyotypes
is due to a replacement
by regeneration
of normal cells.
In reply, DR. CIJRTIS said that evidence is accumulating
to indicate that if a cell is not asked to undergo division,
deoxyribonucleic
acid (DNA) structure
can apparently
reconstitute itself. The exact mechanism of this, of course,
is not known.
Recently,
Dr. Howard
at Yale has actually
identified the presence of certain fragments—the thymine
dimers from DNA, which apparently
can be broken off
either by irradiation or spontaneously—and
he has identi
fled enzyme systems which will rebuild the chromosome if
the cell does not have to undergo division.
If the defec
sometimes
persist in migrants
but frequently
change in
tive chromosome does not prevent cell division, the defect
their children?
is presumably
carried on ad infinitum.
The fact that
Dr. Miller has offered one possible explanation involving
mutations
are due to molecular instability
gives great
enzymatic activity in relation to the metabolism of car
hope for the cancer problem.
As more is learned about the
cinogens.
Other explanations
could involve immuno
forces which stabilize these molecules and heal them, if
logic factors or possibly viral agents.
they are broken, ways will be found to increase their sta
Before beginning the discussion of the papers of Drs.
bility and hopefully to prevent cancer formation.
Curtis, Eckardt,
and Nelson, a brief summarization
of
In reply to the question as to how many times a cell can
some of the salient facts presented appeared advisable.
multiply of its own momentum,
Dr. Curtis referred to
First, there is a broad spectrum of chemical and physical
Demerec, who reported 12 cell divisions in a biochemically
agents in our environment that can induce cancer in labora
deficient mutant induced by radiation in bacteria.
The
tory animals.
Second, marked variations in species' sus
mutant becomes apparent after 12 cell divisions.
In hu
ceptibility
have been identified.
Third, the metabolic
man-cell tissue culture, Puck has regularly observed about
alteration of environmental
carcinogens either can be in 3—4cell divisions after radiation, following which the cell
the direction of detoxification or may involve the in vivo may disintegrate.
Dr. Curtis' work indicates that cells
1317
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1318
Cancer Research
average about 4 divisions following a lethal mutation
fore they are eliminated
from the cell population.
be
Dit. LILIENFELD inquired as to whether the mutational
hypothesis, which essentially relates to the aging hypothe
sis, could be applied to cancer.
If so, humans with cancer
would have an increased frequency of other diseases asso
ciated with aging, but so far as is known, they do not. For
example, according to Dr. Curtis' reasoning, one would cx
pect more
coronary
disease
among
breast
cancer
patients
than among a control group.
Dr. Lilienfeld doubted that
this was true, though it must be admitted there have not
been many systematic observations.
Du. CURTIS replied that such associations do occur in
animals.
For example, if rats are subjected to a low tem
perature,
so that
their metabolism
is increased
to maintain
their body temperature,
they tend to have an increased
rate of induction of all diseases, including cancer and heart
disease.
In a sense, low temperature acts in the same way
that radiation does.
Disagreement
was expressed
with
Dr.
Curtis'
response
to Dr. Lilienfeld's question, namely, specifically whether
other diseases of aging are more common than usual
among patients with cancer.
It was suggested that this
would be true if there were a generalized cytotoxin to
which all cells of the organism were exposed ; however,
there is no reason why any tissue other than the organ in
question should be involved in an increased number of
chromosomal
aberrations.
The relationship between cancer and other diseases was
emphasized as a matter of importance.
A question was
directed to Mr. Haenszel—whether it was true that the
survival of cancer patients is similar to that of other people
of the same age and sex if deaths due to the specific cancer
involved are discounted.
In reply, MR. HAENSZEL noted that the survival figures
of treated cancer patients, who exhibit an excessive mor
tality in the years immediately after diagnosis for several
cancer
sites,
with
the notable
exception
of the breast,
about the 6th to 7th year begin to approach
general
population.
Most
at
those for the
of the disadvantage
in survival
experience is traceable to excess mortality from the cancer
that has been diagnosed.
The evidence suggests that
cancer
patients
as a group
are no more
liable
than
other
persons of like age and sex in the general population to
death from causes other than the cancer and its direct
effects.
DR. SHIMKIN remarked
velopment
concerning
that there is an interesting
2 , 7-acetylaminofluorene
de
which may
have epidemiologic implications.
This compound pro
duces glandular carcinoma in the stomach of rats when in
jected i.p. or when given orally.
Recent work with radio
active
labeling
shows
that
the compound
is deposited
in
the basal layer of the gastric epithelium, a circumstance
which suggests that in the epidemiology of gastrointestinal
cancer one should not concentrate on dietary carcinogens
alone.
He further noted that nothing has been said about some
very
important
&histosoma
human
carcinogens
haematobium,
it. is associated
with cancer
must
a carcinogen
contain
related
to parasites.
about which we only know that
of the bladder
in human
or a cocarcinogen.
beings,
There is
Vol.25,September1965
also a suggestion that Clonorchis sinensis infestation may
have something to do with hepatomas in man. Although
millions of people are exposed to these agents, studies of
the organisms have received little attention in the labora
tory.
The question of using metabolic studies for variations in
populations
at increased
risk in order
to distinguish
the
susceptible from the nonsusceptible was discussed.
The
question pertains to the promotion of studies similar in aim
to that undertaken, for example, the identification of ab
sorption
of cigarette
smoke
in terms
of acetonitrile
excre
tion.
DR.
MILLER
emphasized
that
this
was
a very
difficult
question to answer because one would have to specify the
type of metabolic alteration one would look for. At pres
ent investigators just do not know the crucial metabolic
differences between any tumor and its tissue of origin.
Recent work shows that the high aerobic glycolysis of
tumors
seems
to be more
related
to
their
progression
than to the nature of the initial step in carcinogenesis, as
Warburg originally proposed. Here reference can be made
to the minimal deviation hepatomas, which are respectable
tumors but show no aerobic glycolysis and are similar in
many
other
respects
to normal
liver. If the question
refers
to other metabolic changes that might be specified, one
may cite the work of Dr. Weisburger and his associates on
the N-hydroxylation
of 2-acetylaminofluorene
by human
beings. The 5 patients he examined, all of whom had
some form of cancer, showed quite wide variations
in
ability to N-hydroxylate
this carcinogen.
This obser
vation may indicate a metabolic difference which, were
these people challenged as they might be in industry by
exposure to carcinogens such as $-naphthylamine,
would
cause them to respond differentially.
At this point, Dr. Miller offered some comments con
cerning the problem of endogenous carcinogens.
Are
there any normal metabolites that might be regarded as
such? When he referred to the orthohydroxylation
of
aromatic amines, he mentioned one particular type of test
in which some orthohydroxyamines
seem to be active fol
lowing the implantation
of pellets in the mouse urinary
bladder.
In this test certain orthohydroxyamines
seem
to be active in producing carcinoma of the bladder in the
mouse. Several other orthohydroxyamine
metabolites of
carcinogenic
amines
are not active
in this test.
When
one
tries other routes of administration
with these active
orthohydroxyamines,
little or no activity is found.
How
ever, in every one of these cases the N-hydroxy metabolite
is carcinogenic.
Nevertheless, there is a class of ortho
hydroxyamines
that are normal metabolites
and that
appear to be carcinogenic in the bladder implantation test.
Here the reference was to the metabolites of tryptophan,
such as 3-hydroxyanthranilic
acid and 3-hydroxykyn
urenin.
Recently
have obtained
numbers
Bryan,
Price,
and Brown
data soon to be published
of animals.
These
data
at Wisconsin
concerning
indicate
that
large
by im
planting 3-hydroxyanthranilic
acid, 3-hydroxykynurenin,
and several other normal metabolites of tryptophan
in
cholesterol pellets in the mouse bladder, one may obtain
highly significant increases in carcinoma.
The observa
tions with respect
to these possible
endogenous
carcinogens
Downloaded from cancerres.aacrjournals.org on April 30, 2017. © 1965 American Association for Cancer Research.
KOTIN—Summary
of Discussion
on Physical-Chemical
Factors
seem to tie iii with the earlier work of Price and Brown,
who found that iii approximately
half of the bladder
to potential
cancer
vented.
It is known where they lie, but they just haven't
been properly studied.
Today an attitude is accepted as far as chemicals are
concerned : they are not wanted in the human diet. It is
an accepted view of the federal government and of others
that if there is a substance in our diet which produces
patients
tryptophan
excretion
they
tested,
metabolism
of these
there
was an abnormality
resulting
various
from
metabolites
in
the
increased
following
a loading
dose of tryptophan.
The goal and scope of the meeting were considered in the
part of the discussion opened by Dn. LEVIN, who felt that
the epidemiologists at this meeting did not rise to some of
the implied challenges, perhaps because 2 different types
of epidemiologic problem were being confused.
There is
the broad question of how one establishes in the human
population a generalization
previously established in an
experimental
situation,
or at least of how one tests for it in
a human population.
It is this very important and by far
more interesting problem that has been discussed at this
meeting.
But there is another part of epidemiology which
must not be escaped : upon what criteria does one either
accept
or reject
implications
from
the experimental
laboratory as applying to human beings also? Does one
demand that they be duplicated in a human population,
and if not, what does one require?
DR. BRESLOW commented
that one of the functions
of
such
studies,
tumors
same
sort
vestigation
one
large
state
the
percentage
exceeds
the
undoubtedly
the population
derived
could
shouldn't
from
be pre
be allowed
The question now is : “Shouldthere be the
of attitude
towards
some
of the viral
agents,
and what is to be done about drugs administered
by
medical centers?― Where should the line be drawn and
what do we advise the profession to do? Isoniazid
produces tumors in several species of animal.
Are the
epidemiologists going after all patients treated with this
drug?
It's really no problem to do so. This group could
get extremely esoteric, but there is a practical problem
before it. It is far easier to define the applied problems
with which epidemiologists could be involved than it is to
define more academic problems.
In summarizing
the session DR. K0TIN emphasized
that both the organizers of the meeting and the program
ill
least
By information
cancers
in an animal,
committee
at
many
to consume it.
epidemiology is to provide information to public health
administrators
from time to time for decisions they must
make with respect to potential health hazards, such as the
percentage
of hydrocarbons
in milk. As more refined
methods
of analysis have become available,
federal
agencies have suggested that a certain amount of such
hydrocarbons is permissible in milk. The difficulty is that
permissible level proposed, which means that in that state
no milk should be sold. What does the public health
administrator
for that state do? These are the kind of
problems that are faced and that are going to increase in
frequency
with respect to other possible carcinogenic
compounds.
This subject was further discussed by DR. SHUBIK who
observed that there is a whole series of occupational
cancers which are not being studied anywhere.
It is still
unknown whether coal tar, which produces cancers other
than skin cancer in laboratory animals, does the same in
man. There is virtually no data on human exposure to
catalytically
cracked oils. It is known that skin cancer
occurs and other cancers are being investigated, but there
is no knowledge what their incidence is at present.
Data
pertaining
to the carcinogenic
effects of exposure to
aromatic amines is available, but some of the best data
have never been published.
All the epidemiologists alive
today could be extremely well employed were they to
provide definitive data on present occupational exposures
carcinogens.
1319
had taken
a too long delayed
step in the direc
tion of facilitating
information
exchange between in
vestigators from 2 so-called distantly related disciplines
by enabling them to meet in a seminar-like environment..
The papers presented and the discussion that followed
contributed
to reducing the dimensions of the artificial
barriers that exist between experimental
laboratory
in
and epidemiologic
studies
in the field of neo
plastic disease.
Epidemiologic
studies of cancer have
identified numerous patterns in cancer incidence in dif
ferent areas of the world.
Similarities and contrasts in
risk of cancer associated
with geographic
and other
environmental factors can ultimately be explained only on
a fundamental
biologic basis assessing the roles of both
endogenous
and exogenous factors.
The experimental
laboratory
worker recognizes that his contributions
to
resolving many of the problems associated with etiology,
treatment,
and
control
of cancer
have
pertinence
to the
extent that they are compatible with findings related to
the pathogenesis and natural history of cancer as it is seen
in man. The epidemiologist, in contrast, has been overly
patient in awaiting the utilization of his observations in
the design of laboratory
experiments,
particularly
with
respect to influences more subtle than such obvious ones as
aromatic
amines
in relation
to bladder
cancer
and cigarette
smoking to lung cancer.
The latter happily represent the
acme in the union of laboratory and epidemiologic findings
all directed to cancer control.
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Summary of the Informal Discussion on Physical-Chemical
Factors
Paul Kotin
Cancer Res 1965;25:1317-1319.
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