SCIENTIFIC - MEDICINE, VIRUSES, CANCER

• Document Type: CREST
• Collection: General CIA Records
• Document Number (FOIA) /ESDN (CREST): CIA-RDP80-00809A000700140349-8
• Release Decision: RIPPUB
• Original Classification: R
• Document Page Count: 7
• Document Creation Date: December 22, 2016
• Document Release Date: August 8, 2011
• Sequence Number: 349
• Publication Date: November 10, 1953
• Content Type: REPORT

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WHERE
PUBLISHED Moscow
DATE
PUBLISHED Jan/Fob 1y52
LANGUAGE Russian
HOW
PUBLISHED Bimonthly pert
COUNTRY USSR
SUBJECT Scientific - Medicine, viruses, cancer
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EPORT N0.
ETIOLOGY AI1D PATHOGENESIS OF CANCER
IN THE LIGRT OF IMN,UNOLOGICAL EXPERIMENTATION
L. A. Zi1'ber, Active b:ember
Acad Med Sci USSR (1?to:;cow)
During the pact few years the study of the etiology of malignant tamers i~as
disclosed iw ny important t'acts which cast light on those aspects of this problem
which have continued to remain obscure over a long period of time. It is well
known that, of the nwnercus theories dealing with cancer, the most intensively
devel;,ped Burin; the past decade have been the chemical and virus theories.
The chemical theory arose a long time ago as a result of observations on
occupational cancer and has led to an rlccumul:ltion of a tremendous amount of
data, which seem to prove beyond any doubt the ro.'.e of chemical substances in
the formaticn of tumors. At present, there ar.: kn:.wn many chemically pure, syn-
thetic substances, the introduction of which Llto the organism of animals leads
to the formation of tumors. The caneerogenic ?ictivity of some of them (e.g.
dimethylbenaanthracene, :nethylcholanthrene) is so high that even a single dose
of s fraction of a milligram results 1n the f r.^action of a tumor. Belief in the
chemical theory has grown especially since it was determined that caneerogenic
substances can be formed in the organism from the normal products of cellul:li?
metabolism and since substances of this kind have been extracted from cancerous
tissue (Shabad).
Rowever, the chemical theory of the origin of tumors has met with :. nu~loer
cf difficulties which it has been unable to overcame. During the course o; study
c;f the factors leading to the formation of tumors, the number of difficulties has
continued to increase. Tt developed that, aside from caneerogenic substances,
cancer can develup as a result of the action of radium, Roentgen, or ultraviolet
rays; upon the introduction into 'the organism of sex hormones, arsenic, or dis-
tillates of tobacco and coffee; upon repeated burns; upon the penetration into
the tissues of certain norms; as a result of ulcers and erosion; after prolonged
mechanical irritation; and even after repeated introduction of glucose !ind fructose.
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It is obvious that substances and irritations which vary as widely as these
cannot all be the direct cause of cancer. Thus, the chemical theory of the origin
of tamers could.not serve as a rational explanation for the extraordinary variety
of factors, the action of which on the organism is followed by the inception of
cancer.
very prolonged action of such an active cancerogenic substance as methylcholan-
threne does not result in the formation of tumor cells in tissue cultures, i.e.,
cells which upon implantation into the organism could have induced development
The virus theory has also encountered difficulties. First stated by t?iechni-
kov and Borrel prior to the discovery of tumor viruses this theory developed very
slowly, meeting with comple*.e apathy on the part of the medical world. However,
facts obtained in the study of cancer from the point of view of the virus theory
attracted increasing attention and at present the virus theory is cf interest to
the widest circle of physicians.
ldost pertinent have been facts obtained in the study of cancer of the lactic
glands of mice. The stimulus in this disease proved to be a special virus trans-
ferred with the milk from the mother to its young. Mice are sensitive to this
virus only during the first 2-3 weeks of their lives. Ewen when a very large
quantity of this virus is introduced into a mature mouse, the animal does not
develop cancer, though it remains a carrier of the virus throughout its entire
life. A necessary condition for becoming diseased through the introduction of
the virus into the organism is pregnancy. A mouse that has not been fertilized
does not get cancer, even though it has received the virus during the first few
weeks of its life.
All these data attest to the fact that the virus of cancer of the lactic
glands of mice is only very slightly pathogenic. A niuuber of conditions are
required far it to manifest its action.
At present, there are numerous tumor-producing viruses which are reliably
known to cause tumors also in other animals, such as rabbits, chickens, ducks,
frogs, and fish. The ma,~ority of these tumors had to be photographed with the
help of the electron microscope, while a few oi' them, including cancer of the
lactic glands of mice, are visible under the optical microscope (Morozov, Bayda-
kova). As other viruses, tumor viruses in the mn.?ority of cases are spherical
in shape and resemble the coccus forms of bacteria. However, there are relatively
few tumors whose virus etiology has been reliably established. In the majority
of tumors both in tiwrans and in animals, no vin~ses capable of causing the forma-
tion of such twnors co~ild be found, This fact is the main obstacle to the uni-
versal acceptance of the virus theory.
The inability to isolate viruses from the majority of tumors has been vari-
ously explained. It is known that 1t is easy to obtain the virus serving as the
inducer of rabbit papi)'.~ma? Ilowever, as soon as the papilloma becomes malignant,
the virus can no longer be detected; it assumes what is known as a "masked" form.
:;imil.a r masking is Y.nown for other infectious viruses. Thus, the influenza virus,
upon combining in the form of complex compounds with certain enzymes, completely
loses its activity and regains it only after the breakdown of the complex. It is
possible that failures to isolate viruses from the majority of tumors are thus
due to the fact that the viruses are present in ~. masked form.
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...,
It is also possible that a special method not yet discovered would be required
to isolate viruses Prom the majority of tumors. The special characteristics of
the virus of cancer of the lactic glands, which can be isolated only under certain
conditions are pointed out above. The method by xhich this virus was detected has
not y,?t been applied to the study of other tumors and it is possible that with the
help of this or oP some other method, other viruses as well will be isolated. The
advantage oP applying this method of research has been confirmed by a recent com-
munication by Yablonovskaya, who, by using the chorioallantois membrane of the
chicken embryo as a medium, isolated a virus-like agent from several tumors of
the central nervous system.
All the reasons cited to explain the lack of success in isolating viruses
from the majority of tumors are based on experimental data. But these reasons
are still merely conjectural, If viruses serve as etiological factors for tumors
and are actually contained in them, even though in a masked form, they should be
detectable in cancers as a foreign protein. Actually, each virus is made up
principally of protein which is foreign to the organism in which the virus has
developed. Under such circumstances, when the virus cannot be detected by its
pathogenic action as a bioloical agent, the protein substance of vhich the virus
is .composed should be detectable by immunological reactions as an antigen Poreign
to the .organism. Immunological reactions are the most sensitive of all reactions
known up to now, disclosing the presence of proteins and determining their speci-
fic nature. It ie for this reason that they are widely used in forensic medicine
for an enact determination of type attributes of blood and other proteins.
Consequently, it would be quite natural to try to eliminate those obstacles
which are encountered by the virus theory of the origin of cancer by means of
LnmunoloPical experLmentsticn.
Over the course of ninny years, our attempts to find in tumors which are not
transmitted by filtrates any sort of foreign protein have not met vith success.
Our failure, as later research showed, was due to the small concentration oP
this protein in tumors and to insufficient sensitivity of the usual immunological
reactions. Inasmuch as viruses basically consist of nucleoprotelds, we studied
nucleoproteid frnctl~ns from tu.-nor tissues, hoping that they would contain more
of the tumor virus than the entire mass of tumor tissue. With the help of the
complement-fixation reaction and of precipitation, we were able to establish the
presence of e specific tumor antigen in these fractions.
Aowever, as shown by erperimetits with tumors in which the virus is easily
detected by means of a biological test (chicken sarcoma), the nucleoproteid
fractions of tumor tissue as well as the substance of the tumor virus also con-
tained protein substance~? of normal tissue. For this reason, the results obtained
would not permit a clear and infnllibie differentiation between qualitative char-
acteristics of antigens from tumorous cells acid antigens of normal cells.
Inasmuch as attempts to obtain the virus protein in a form sufficiently free
of proteins from normal tissue proved fruitless, we developed a special reaction
w}~ich came to be culled the renction of anaphylaxis with desensitization; this
renction permitted the detection of the spec ifir_ substances of tumors even when
found in n mixture with proteins from normal tissue,
The nature of the reaction is ns fol.lcws. Guinea pigs are injected subcuta-
neously with a fixed numL?er of milligrams of the nucleoproteid fractions obtained
from tumor tissue, e.g,, from cancer of the liver. It is known that guinea pigs
who receive a certain protein parenterally become highly sensitive to it and re-
spond by means of an anaphylactic shock to its repeated infection. If the guinea
pigs survive this shock, they do not react to any further introduction of this
particular protein. Zn other words, the first infection of protein sensitizes
them; while repeated injection (if they survice)desenaitizes them to this
protein,
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Upon having received a nucleoproteid fraction Prom a cancerous liver, a
guinea pig becomes highly sensitive to the injection of nucleoproteid. Simi-
lar experiments show that it is sensitive even to nucleoproteid from a healthy
liver. To learn whether a nucleoproteid from a cancerous liver contains a sub-
stance absent from a nucleoproteid fraction of a healthy liver, the following
procedure is employed. A guinea pig sensitized with a cancerous fraction can
be desensitized by a fraction removed from normal tissue. After this, it should
not react to a nucleoproteid fraction from normal tissue. In order to test this
hypothesis this fraction is once more introduced into the guinea pig, but this
time in a larger dose.
If this test for the full degree of desensitization proves successful and if
the guinea pig does not react to the final jincreasedj test dose, it is given a
nucleoproteid fraction from cancerous tissue, in the given case from cancerous
tissue, in the given case from cancerous liver, in a dose which does not exceed
the dose used in testing for the full degree of desensitization. As a rule, the
guinea pig responds characteristically to this, sometimes by a fatal anaphylactic
shock. This seemingly attests to the fact that there is a substance in tumor tis-
sue which is absent frcm normal tissue.
These experiments, carried out together with a number of my colleagues (Nar-
tsissov, Raydakova, Farnes, Gorodilova, Shershul'skaya, Radzikhovskaya, Freyman,
Gardash'yan, Avenirova, etc.), showed that the reaction of anaphylaxis with desen-
sitization discloses specific substances in all investigated tumors. At present,
they have been discsos~-~? in r..an in tumors of mist varied localizations, in tumors
of mon}:eys induced b r. ran^eroF;?nit factor, and ir. various tumors of rabbits, rats,
mice and r.h1r.Y.ens. ThesF include both spontaneous and induced as well as trans-
plan~ed tumors.
The tremendous amount of material which has accumulated concerning this
question at the institute imer.i I7. F. Gamaleya and the Central Ontological
Institute irreni F. A. Gert.sen is supplemented by the findings of Dyad'kora
(Institute of One'~ingy of the Academy of Medical Sciences USSR), which disclose
the presence of a soer.ific substance in induced tumors of chickens, and also the
findings of Rapopcrt (Institute of Neurosurgery imeni N. N. Burdenko), who was
the first to discover the specific substance in tumors of the central nervous
system. Finally, there was recently published the xork of Ginzburg and her
colleagues, Ioffe, Rozent.al', Larionov, Smoylovskaya, and Medvedev, who also
detected the specific substance in tumors with the aid of the reaction of com-
plement fixation.
It is necessary to point out that a special commission of the Academy of
tdedical Sciences USSR composed of L. td. Shabad, N. N. Zhukov-Verezhnikov, M. M.
Mayevskiy, Y. i1. Kosyakov, N. M. t+ledvedev, anfl others made a special check of
our investigations disclosing the specific substance in tumors, and completely
verified our results.
Thus, *.his question, the study of which via begun by us as early as 1936,
may be ecnsidered to be conclusively resolved. idalignant tumors contain pro-
teir. substances (specific antigens) which are absent frcm normal tissues.
',lust are these antigens: arc they viras substances, the detection of which
is the problem of cur researchers, or, pcsoibly, are they a special protein cre-
ated as a result of disrupticu of the process ::' synthesis occurring during can-'
cer'i The possibility of sur_h ,:isruption and the creation of a special tumor
protein was confirmed by a number of studies by V. I. Zzbarslciy.
The problem of the nature irf specific antigens of tumors proved to be
very ccmplex and cannot be considered as having been solved yet. However, the
data obtained lend to a number of prem.'.ses most essential for considering the
pathogenesis of tumors.
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First of all, there was investigated the quesiion cahether the virus contains
specific antigens ~hether the specific antigens contain virusY7 when the antigens
are being given off by n tumor the virus etiology of which has been definitely
established. Corresponding experiments (Radzikhovskaya) have sho~.m that even
0.005 milligram of a specific antigen removed from chicken sarcoma contains an
active virus which is capable of producing the same tumor.
actually permits the extraction of the virus protein is a concentrated form if
the virus is contained in the tumor. This has been confirmed by experiments on
the immunization of nrimals with specific antigens from tumors. Experiments in
All these data permit us to state with certainty that specific antigens fil-
tered from tumors actually contain a protein which is a virus substance.
A rather important factor, making it possible to extend this conclusion to
specific antigen6 from tumors in which viruses were not directly discovered, was
the prer,ise establlsYur.ent of the fact that these antigens were foreign to the
organism from the tumor of which they were removed (ttartsissov).
It is difficult t:o grant, for example, that the human organism can synthe-
size a nonhuman protein, one which is foreign to it. In cases where such a pro-
tein was detecte3, it was always the prctein o;' a infectious agent which had pene-
trated into the organism frcm outside.
However, `here are also 'mown cases of disnrption of protein synthesis in
the organism w'nen there is being synthesized rot a foreign protein but one dif-
fering fr~,m the n:~nnal un:? neraa'.iy `bsert :ras the organism. This process occurs,
fbr example, in the form~:tion of ::aft};od=es. Tice antigen entering a cell of the
reticulo-endothe'_ircn disrupt,:; ?.hc synthesis F;iebul:ns while the modified glo-
bulins being frr^ned in ,.his tonne^_tion are ,:nobodies.
It could be quite .slurs? to rsise t'.:e cu?~tion whether there do not also
enter into the c~;ml:os;t.;~cn of the cp?c ills tamer antigens detected by us modi-
lied globulins r:f i,hr cry;:nn'iam :: ;vci, could be produced as a result of the action
of the virus r_n tL?e r11 slid di ;r.rpti~n by tiro virus of the processes of synthesis.
At present, we have ohtnined in ?:arr ].nborutory a number of indirect data giving
evidence of such a possibility
In studies making use o: the reaction o anaphylar.is with desensitization
for nucleoproteid fractions, investigation o:' a:nyloid spleens of patients who
died of tuberculosis disclosed ;hat, there are contained in the spleens three
types of antigens: a species and or,;an ano~;en, a tuberculous antigen, and an
amyloid antigen. The amyloid anti?;en is absent from the spleens of healthy per-
sons but iL has been found in the spleens of rersons who died from chronic sep-
sis.
The..^,e data rr~w ... _., the ,ho'_r:air.:_ ;toss can induce a disruption of
t7etnbolism in the :,rganisn ::hick is accompanied by the synthesis of modified
proteins differ en+, from those oi' a normal or~ar,ism.
It is quite probable that a comparable process also tares place in cancer.
'.Phe soli which is affer_ted by the tumor virus preserves for a long time the
character of its protein synthesis, but there comes a time when the regulatory.
functions prove inadEquate, the synthesis of the prctein is modified, and there
is produced in the'cel]. a pro+.e in which differs from the normal.
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Fundamentally, this is evidently the malignant process. Regulatory devices
of the organism directed by the central nervous system prove inadequate for the
cells with modified protein and for this reason a progressive growth of these
cells begins, resulting in the formation of a tumor.,
It is quite probable that starting from the moment of the formation of csn-
cer protein the role of the virus changes considerably. In as far as the virus
induces the indicated change in metabolism, it is possible to hold that it has
a special affinity to the cancerous protein and is blocked by it in the same way
that the antigen is blocked by the antibody formed as a result of the change in
metabolism in the cells induced by this antigen. However it may be, the forma-
tion of a cancer protein as a result of the action of the virus on the cell repre-
sents one of the most Lmportart steps in the pathogenesis of cancer.
If need not be remaY.ed that what has been stated above is only a working
hypothesis developed during the course of our experiments. Hypotheses of this
type are necessary in studying such a complex problem as that of the etiology
and pathogenesis of cancer. IJevertheless, we would sot have decided to fonm3-
late it if, on the one hand, we di3 not have the above-described indirect data
on which this hypothesis could be based and, on the other head, if we did not
see the way to check it experimentally. Further investigation will make it pos-
sible either to ^_onfirm or to re,jecS !t.
At present, rt Ss important that this hypothesis opens up to us new possibili-
ties for the study c,f cancer,
Our experiments of preceflin;; years definitely established that immunity to
the tumor virus and immunity to the tumor roll are dependent on different mech-
anisms. This position ?.ra: recently confirmed in the experiments of Radzikhovskaya
with chicken sarcoma. ;dith considerable certainty, we now can assume that this mech-
anism in the first case is directed at the neutralization of the virus antigen
and in the second case to ?he ..*.eu!ruiizatior, of the antigen of the cancer protein.
Since the problem of obtaining an artificial im:aunity to the terror virus may now
be considered as hav+ni~ been res~l.ved i^ principle, ve can broach the task of
producing au artifici:,l rmmur.ity t.c tumor cells by utilizing antigens of the
cancerous protein. 'These still limited data which we now have at our disposal
and which pertain to t?.ru different tumors ca',:c it possible to ?hink not only of
the considerable instability of such antigens Lut also of the possibility of
still producing r:n art ifl,ial ;rJnunity to the cancer cell. It is hardly nece~-
sary to speak of the tremer:dcus practical sign ificanr_e of an exhaustive solution
to this problr'm.
Ghat has been described above mai;es possible the following brief formulation
of n hypothesis concerning the o r gin of cancer. Twnor viruses penetrate into
the organism from without. The manner o? this penetration has so far been studied
for two kinds of tumors: rabbzt papillemae, the virus of which is transmitted by
t1cYs, and cancer of the lsctic gland of m`ce, the virus of which is transmitted
by milk. Twnor vinrses entering the organism do not manifest their disease-pro-
ducing power :or a very long time. This is because of weakness of 4he disease-
producing power for the greet majority of such viruses and the necessity for the
fulfillment of r. number of cund~tiors for its manifestation.
One of the Iirincipal conditions is the creation zn the organism of centers
of cell proliferation. This is the manner in which numerous carcinogenic sub-
stances and reactions exert their action. In spite of the wide variety of their
neture; all of t},em induce proliferating processes and metaplasia of tissue result-
ing in the formation of a large number of young, not completely typical, cells.
Thus, all these cuneero~enic substances and reactions are not etiological but
pathogenetic factors. They create in Ghe organism conditions in which the already
present virus can manifest its pathogenir_ activity.
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The virus, having penetrated into the proliferating cells, disrupts the prac-
eas of metabolism taking place in them and thus modifies the synthesis of protein.
As a result of this, cells are produced with a protein which differs from the nor-
mal. This is basically the process of malignant growth. Inasmuch as the instru-
mentq regulating the growth of cells were created in the process of evolution
with respect to cells with normal protein, they prove to be inadequate in regard
to cells whose protein has been modified and has become cancerous. For this ren-
son an intensified multiplication of these cells begins, resulting in the forma-
tion of a tumor.
The virus, having disturbed the synthesis of protein in the cell, in the
majority of cases is blocked by the newly formed protein and for this reason
cannot be detected in the tumor by the usual methods.
This hypothesis considers the origin of a tumor as a complex chain process.
Certain lin}:s in this process are accessible to immunologica'_ analysis at pres-
ent, thanks to our research and can be artificially inactivated by immunological
reactions.
The basic problem of further research consists in the immunological study
of the process of malignant growth and the artificial creation of immunity to the
tumor cell.
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