the problem of malignant tumor growth
DESCRIPTION
The problem of malignant tumor growth. A fundamentally new solutionTRANSCRIPT
Oleksandr Shevchenko Volodymyr Shevchenko Viktor Shevchenko
TThhee pprroobblleemm ooff mmaalliiggnnaanntt ttuummoorr ggrroowwtthh
AA ffuunnddaammeennttaallllyy nneeww ssoolluuttiioonn
Kyiv 2009
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УДК 616 ББК 55.6 Ш 38
Shevchenko O.V., Shevchenko Vol. O., Shevchenko V.O. The problem of malignant tumor growth. A fundamentally new solution. (Translated from Ukrainian). – 22000099.. –– 7722 рр..
In 1970-ies in the former Soviet Union in Kyiv (Ukraine) an
efficacious immunological method for malignant tumors’ treatment was created.
The complete recovery from transplanted and spontaneous malignant tumors (even at the IVth stage of the disease) was attained in a significant percent of cases in animals.
Attempts to treat patients with tumors by means of this method yielded hopeful results.
The number of unique biological phenomena that had never been described in science before were observed in individuals cured by the new method:
• their blood serum gained therapeutic antitumor properties that were manifested in allogenic and xenogenic systems;
• in the treated individuals their regenerative abilities have considerably increased (up to organotypical regeneration);
• their organisms’ rejuvenescence as well as some other phenomena were observed and the others.
In this book the scientists who participated in the research conducted, describe the results obtained and provide them with scientific explanation.
© Shevchenko O.V., Shevchenko Vol. O., Shevchenko V.O. 2009 Gnosis, 2009
ISBN 5-311-01319-2
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Dedicated to the blessed memory of our relations: Zhana Shevchenko, Sita Bezpalko and Svitlana Bezpalko, who suffered from malignant tumors
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Acknowledgement The authors express a sincere gratitude:
• To the President of Ukraine’s adviser, Academician Petro Tronko who, while holding an office of the First Vice-Prime-Minister at the Government of Ukraine rendered an organizing support for the research described in this publication.
• To the director of Academician V.Komisarenko Scientific Research Institute of Endocrinology and Metabolism, a Corresponding Member at the Academy of Medical Science of Ukraine Mykola Tronko, who participated in the check experiment in 1970-ies.
• To Liubov Rachinska who was kind to provide us with some materials from Vitali Rachinsky’s archives that represent the results of the experiments conducted.
• To the politician Vasil Volga (Kyiv) and to the businessman Evgeni Gavrilov (Moscow) for the sponsor's support in publishing the present book.
• To Bela Men for translating the manuscript of the book into English.
And also to everyone who rendered moral or organizing assistance during all the period of theoretical and practical researches as well as in preparing the book.
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CONTENTS
INTRODUCTION
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REVERSION OF MALIGNANT TUMOR PROCESS: THE RESULTS OF STUDIES AND OBSERVATIONS CARRIED OUT
8
The results of malignant tumors’ treatment in animals
8
The results of clinical observations 28
METHOD OF MAKING AND APPLICATION OF ANTITUMOR DRUG “NEOREVERSIN”
36
THEORY: A FUNDAMENTALLY NEW VISION OF AN ORGANISM′S IMMUNE REACTION IN PATHOGENESIS OF MALIGNANT TUMORS
38
Specific immune reaction of organism as initiator and promoter of carcinogenesis
38
Discussion 59
GENERAL CONCLUSIONS
67
THE PROSPECTS OF IMPLEMENTATION
68
APPEAL
70
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INTRODUCTION
In the early seventies of the last century Zoya P.Uspenska, a kyivite phthisiologist, created an immunological method for malignant tumors’ treatment, based on placental extract, by means of which a significant percent of cases of implanted and spontaneous malignant tumors in animals at their generalization stage as well as in oncology patients with neoplastic process at stage IV were successfully completely cured.
The immunological antitumor drug applied acquired its conventional title as Reversin.
In the middle of 1977 Z.Uspenska’s co-operation with the authors of the present work began that had been going on in different forms for 9 years (until Z.Uspenska’s death).
The results obtained aroused a wide interest in the circle of physicians, biologists and some administrative authorities (KGB of the former USSR, in particular).
Several competent commissions were set up to check the findings of Z.Uspenska and her co-workers with the participation of distinguished scientists: biologists, immunologists and oncologists. Among them were the world-known scientists (Academicians A.P.Avtsyn, O.V.Baroyan and V.P.Komisarenko). They familiarized themselves with the results of the work performed and gave them a high scientific appreciation, having pointed out to the good perspectives and the necessity to proceed with further research in this direction.
Despite an active support of the above, there have never been any financial or organizing measures taken that would be necessary to expand the research in this sphere. In 1984 Z.Uspenska’s Laboratory was disbanded and the creative team was broken up.
There were a number of reasons for that: • First, the most serious obstacle to develop scientific
studies in this area was a striking lack of coincidence between the results obtained and the scientific notions existing at that time (and to a considerable extent, at present) of the essence of oncology process and the possible ways to influence it.
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No theoretical concept has even been proposed, on the grounds of which one could explain the whole range of the unique results obtained.
• In the second place, all the researches on the treatment of oncology diseases by the given method were made secret at that time which excluded the opportunity to familiarize scientific public at large in the former USSR with them, to say nothing of the foreign public.
• Thirdly, Z.Uspenska did not let anybody in on the details of producing the Reversin drug, which confined the opportunity to study its effect to one laboratory only.
On May 29, 1986 Z.Uspenska died without revealing the technology of the drug’s production. Nevertheless, the research in this area was carried on by
the authors as we were the most closely associated with her work, by conducting the experiments on animals, participating in people’s treatment, etc.
The researches were aimed at restoring the drug’s production technology as well as elaborating the theory of its therapeutic effect.
As a result, the work of the informal scientific team, consisting of Oleksandr Shevchenko, Volodymyr Shevchenko and Viktor Shevchenko, has been accomplished at the creation of an antitumor immunological medicine, called “Neoreversin” which, according to the preliminary experimental study results, has the properties close to the Reversin drug used before by Z.Uspenska.
A new vision of the role played by an organism’s immune system in shaping the malignant tumor process was scientifically substantiated, in light of which an explanation of most of the phenomena that had been observed in the conducted research was made possible, and primarily, the phenomenon of the reversion of malignant tumor process.
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REVERSION OF MALIGNANT TUMOR PROCESS: THE RESULTS OF STUDIES
AND OBSERVATIONS CARRIED OUT
THE RESULTS OF MALIGNANT TUMORS’ TREATMENT IN ANIMALS
The results of treating rabbits Methods
Experimental study of the Reversin’s antitumor properties was begun on rabbits with implanted Brown–Pearce carcinoma.
Rabbits were administered a single subcutaneous Reversin injection at the time when the signs of generalization of the tumor process became apparently clear i.e.: the loss of appetite and flesh, tumor metastatic nodes being palpable in abdomen and under the skin or visualized in eyes. Experiments on rabbits were conducted as from 1971 through 1980 in various research institutions. The experiments’ results are summarized in the table shown below (Table 1).
The efficacy of treatment was estimated by the following criteria:
• the animals’ lifespan: the treatment was considered efficient if the treated rabbits were still alive after the last animal in the control group had died. Control animals usually died during a month following the tumor implantation;
• the animals’ physical status: the rabbits that had recovered became more active, they had their appetite resumed, the tumor nodes began diminishing and finally completely disappeared. Also the animals put on weight;
• on the basis of pathologicoanatomic examination, carried out in different time periods since the beginning of treatment, depending on the undertaken task. In conducting the check tests all the animals that survived (both the treated ones and those untreated) were generally sacrificed.
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Summary table of the results obtained in Reversin-treated rabbits with implanted Brown–Pearce carcinoma.
Number of animals in a test group
(The animals were treated)
Number of animals in a
control group (The animals not
treated) Died
Place of the conducting experiments
Dat
e of
exp
erim
ents
con
duct
ion
At t
he s
tart
of t
he
trea
tmen
t
Surv
ived
Die
d fr
om tu
mor
Die
d fo
r oth
er
reas
ons
At t
he s
tart
of t
he
expe
rimen
t
Surv
ived
Die
d
Institute for Oncology
Problems of the Academy of
Sciences of the UkrSSR (Kyiv)
1971 and
1973.
51
37
11
3
25
__
25
Institute of Microbiology and Virology of the Academy of
Sciences of the UkrSSR (Kyiv)
1971, 1972, 1973.
70
57
13
___
52
__
52
Institute of Molecular Biology and Genetics of the Academy of Sciences of the UkrSSR (Kyiv)
1976, 1977, 1978, 1979, 1980.
98
71
16
11
44
2
42
Institute of Microbiology and Epidemiology of the Academy of
Medical Sciences of the USSR (Moscow)
1977.
5
3
2
___
5
__
5
Total 244 168 42 14 126 2 124
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It is seen from the Table, that 168 out of 224 treated rabbits have recovered, that consist of 75%.
Out of 56 treated rabbits, witch were died in test group the 14 animals differ from other. They died in between the 3rd and 4th months following the beginning of the treatment. The purulent broncho- or pleuropneumonia were found at their autopsy and no signs of tumor process.
If the 14 about mentioned rabbits were included into the number of animals cured from tumors then the percentage of recovery would increase to 81,3%.
The photographs of kidneys and liver of the Reversin-treated rabbit slaughtered at an intermediate stage of recovery from the malignant tumor.
Fig 1. The kidneys affected by metastases of Brown-Pearce carcinoma
The photograph shows small dark hollows in the center of most of metastatic nodes. As it was proved by microscopic examinations these were the zones of hemopoiesis.
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Fig. 2. A section of the rabbit’s liver In the center of metastatic nodes there are the very same
dark zones. Attracting attention is the fact that in the center of the metastatic node, marked with a cross, there are only three tumor fragments left and in between the liver tissue structure can be clearly visible. Assumption: the metastases cells were differentiated into the normal liver cells.
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The results of the experiments conducted on rabbits proved that after a single Reversin injection the regression of tumor and its metastases occurred in the organism, and anatomic integration as well as the functions of the affected organs were completely restored.
Pathologoanatomic examinations, including histological tests conducted on rabbits by V.N. Rachinsky, a fellow-worker of the Laboratory, give grounds to suggest that the Brown – Pearce carcinoma tissues were transformed after the treatment into normal tissues of the organ wherein the primary and metastatic tumor nodes had been present.
As it was shown in further research the blood serum of the rabbits cured of Brown-Pearce carcinoma, some time later (from 7 to 8 months) following the administration of Reversin, had acquired therapeutic antitumor properties that were manifested both in allogenic and xenogenic systems.
This effect was extremely visibly displayed in the experiment conducted by Oleksandr V. Shevchenko, Volodymyr O. Shevchenko and Mykola D. Tronko at Kyiv Scientific Research Institute of Endocrinology and Metabolism.
On December 12, 1977 two Reversin-treated female rabbits, being in the stage of recovery from Brown-Pearce carcinoma, were selected for the experiment. By the beginning of the experiment all the signs of the tumor process had disappeared in both animals except for the residual tumor metastases in the eyes as a greyish–white formation occupying a part of the eye’s iris. The blood of a rabbit, suffering from carcinoma, was dropped into the eyes of both of the rabbits. On the third day after the blood dropping all the signs of malignant process stimulation emerged: the eyeballs began to increase and protrude out of the eye sockets. On December 20, the antitumor serum was started to be dropped into the eyes of one of the rabbits. A week later the tumor regress became already visible. Meanwhile the other rabbit’s progressive tumor continued to grow. On January 7, 1978, the rabbit’s left eyeball projected
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out of the eye socket by 2.5 cm and the right one – by 1,5 cm. The eye lashes were unable to cover the eyes.
That very day the other rabbit also started to undergo
treatment in the same fashion (by the serum dropping into its eyes). Next day the dilated blood vessels were clearly observed in both of its eyes, and some days later a vascular plexus appeared in the shape of a ring around the necrosis zone, formed at the apex of the enlarged left eyeball.
Antiblastic serum was dropped into the rabbits’ eyes for a month’s time – first daily, then every second day and every third day. A gradual resorption of tumors occurred in both rabbits. And by the end of the 4th month since the beginning of the treatment the tumors’ complete regression was achieved. The eyeballs acquired their normal size and shape. Both eyes of the first rabbit and the right eye of the other one resumed their eyes’ normal look with an open pupil. However, on the left eye of the other rabbit wherein there was a large necrosis area, leukoma emerged.
Dynamics of the tumor regression was especially vivid to
occur on the left eye of the second rabbit. This dynamics is presented in a series of figures shown below.
Fig 3. The 2nd day after the beginning of the serum dropping
Both eyes of the rabbit are dramatically projecting out of their eye sockets. The left one juts out by 2,5 cm. It shows a tumor necrosis zone and the dilated blood vessel, which hasn’t been observed prior to the beginning of the treatment.
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Fig 4. The 6th treatment day. The view of the left eyeball
The blood vessels that became more strongly dilated can be clearly observed. Necrosis area is also seen occupying the entire eyeball zone. A demarcation line between the tumor and the necrosis zone starts to be formed.
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Fig 5. The 32nd day since the beginning of the treatment
The left eyeball has been significantly reduced in size and acquired a cone-shaped form. On the cone top there appeared a crust. An intensive vascularization of sclera outer surface and reduction of the necrosis zone can be clearly observed.
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Fig 6. The 52nd day since the beginning of the treatment
The eyeball continues to diminish. There is an intensive vascularization of sclera. The necrosis zone has been reduced, the crust has disappeared.
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Fig 7. The 66th day since the beginning of the treatment. Side view
The necrosis zone has disappeared. The tumor has acquired a compact shape and the closure of eye lashes was made possible. Hypervascularization of the eye is still preserved.
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Fig 8. The 120th day after the beginning of the treatment
The tumor in the eye has completely disappeared. The eyeball has its initial size and form restored, however on the cornea where there was a necrosis zone, leukoma was formed.
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On the 120th day since the date of the treatment start no
indurations were identified in the rabbit’s abdomen at palpation. The rabbit was in the normal physiologic condition.
A year later after the experiment had been conducted the above described rabbit was transferred to Moscow for further investigations.
As it was founded out by the authors, no signs of the undergone neoplastic process were detected at the autopsy and histological analysis of the internals.
When exploring the eyeballs the presence of all the anatomic constituents, characteristic of the normal eye, was stated. Out of pathologic abnormalities there was keratoleukoma.
An impressive result of the experiment was also that the regression of the tumor occurred in the setting of a sharp increase in its vascularization.
New biological phenomena found out in experiments
on rabbits
1. The phenomenon of complete reversion of the malignant tumor process from its generalization stage.
2. The effect of post-convalescent antitumor resistibility. The essence of the phenomenon lies in that the rabbits which have been cured of Brown-Pearce carcinoma by means of Reversin can’t repeatedly take on this tumor.
3. The phenomenon of the blood serum antiblastic activity in rabbits cured of Brown-Pearce carcinoma by means of Reversin.
4. The phenomenon of malignant tumor regression in the setting of a sharp increase in its vascularization.
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The results of treating horses Experiment description
The Reversin drug was also applied to treat 3 horses (two stallions and a mare), suffering from malignant neoplasms – melanosarcoma and melanoblastomatosis. (As is known from the literature, melanotic tumors can be often found in horses of grey breed.)
A stallion “Vodiy”, born in 1961, of the Orlov trotter breed, was examined on 20.05.1973 by the Veterinary Commission, headed by Professor I.O. Povazhenko, being in charge of the Chair of Surgery at Ukrainian Agricultural Academy. A focus of melanosarcoma was detected in the horse in the left prescapular region being two fists size, a melanosarcoma focus on the penis a hen egg size, and a focus of melanosarcoma near the anus being a wall-nut size. On the basis of the disease symptoms found the Commission arrived at the conclusion that it was inexpedient to treat the stallion and it was to be rejected as defective.
At that time a stallion “Amper”, born in 1961, of the Orlov trotter breed was also rejected as defective because of melanosarcoma disease. A great amount of melanoblastomatosis nodes were identified near the anus, a pigeon-egg to a wall-nut size, as well as in the region of the spur vein on the left and in the area of the penis a plum size.
On 14.09.1973 both stallions underwent the treatment with Reversin.
On 4.05.1977 Reversin was also administered to treat a mare “Pokrova”, born in 1958, of the Orlov trotter breed, which was rejected as defective because of melanoblastomatosis disease in the areas of the anus and udder in accordance with the Statement of 14.04.1977. Treatment results
On March 24, 1979 all the three horses were examined by the same Commission that had rejected them as defective. The Commission came to the following conclusion: 1. The stallion “Vodiy” is clinically healthy. At the seat of
the tumor in the left prescapular region there is a small induration of 5 x 7cm size remained, protruding a bit
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over the skin surface. Near the anus there is an induration of 2.5 x 2.5cm having a hollow in the center. The tumor nodes on the penis and in the scapula zone have completely resolved.
2. The stallion “Amper” is clinically healthy. Near the anus the residues of three nodes 0.5x1.0 cm in size can be palpated. The tumor nodes in the area of the penis and the spur vein are completely resolved.
3. The mare “Pokrova” – is in a good state. The tumor nodes near the anus, the udder and on the right of the mandible have completely disappeared. Edemas in the abdomen and udder region have gone. The mare is clinically healthy.
The follow-up term for the stallions made up 5 years, for the mare was 2 years. The Commission made a conclusion of the efficacy of the method applied for the treatment of malignant neoplasms in horses.
It is seen from the above mentioned that complete reversion of the neoplastic process from its generalization stage can be achieved in horses as well by means of Reversin. Biological phenomena, observed in treating horses
Just like in the case with rabbits some concomitant phenomena were also observed with horses cured.
The horses got rejuvenated which was displayed in their renewed capacity for work (they started to be used again for agricultural works to the full) and in their resumed sexual activity, gone out already by the beginning of the treatment as well as in their restored pelage colouring typical to young specimens: dapple - gray, three months after the treatment. This pattern disappears in old horses. They become uniformly light-gray.
This phenomenon, i.e. the organism’s rejuvenescence in horses cured from malignant tumors, can be the basis for the assumption to be made that their lifespan could surpass their average indexes. Speaking in favour of this assumption is the fact that the above described horses when delivered for slaughter (as they reached an average age for the Orlov trotter equal to 22 years old) were still strong and capable of working with sexual activity preserved.
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The results of treating mice
In the experiments carried out on mice, Erlich carcinoma, a classic version of the malignant tumor disease served as a model. A solid tumor process was induced by subcutaneous inoculation in the animals’ back or femur zones of a cancer cells suspension in the form of a peritoneal exudate derived from the abdominal cavity of mice, suffering from ascitic type of carcinoma. Prior to the injection the exudate was diluted by a sterile physiologic salt solution with 1:1 ratio. The experiments were conducted on white, non-thoroughbred animals, as well as on the mice of CBA line. The animals’ treatment started when a tumor node no less than 1cm size in diameter appeared in the place of the cancer cells inoculation.
The attempts to treat mice suffering from the solid carcinoma by means of Reversin yielded no positive results. However, the treatment of mice with antitumor blood serum of the rabbits, cured by means of Reversin, was a success. The serum was administered parenterally to mice. The tumor ceased to be palpable in the experimental animals during the interval between the 20th and 30th days since the beginning of the treatment.
Totally 185 mice were used in the experiments. The recovery of animals occurred in 40 through 60%. Being based upon the findings one can make two conclusions:
• the first one is that mice just like rabbits can also be treated for malignant tumor process by the new method;
• the second one is that in so far as overcoming the tumor process in mice was attained by means of the rabbits’ serum it indicates to the ability of the latter to display antitumor properties not only in allogenic but also in xenogenic systems.
Phenomena observed in experiments on mice
1. The phenomenon of an organism’s expanded regenerative abilities.
It was found out on mice exactly that the range of regeneration processes in animals, cured of malignant
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tumor, can be strongly expanded right up to the possibility of organotypical regeneration.
This phenomenon was not anticipated and it was discovered quite occasionally. A group of mice cured of tumor that were regarded as being worked off, were kept for several months in a vivarium for the purpose of their possible use in other experiments.
During this time period the mice’s tail ends, cut off to collect blood during the experiment, were noticed to grow. The procedure of collecting blood from mice’s tails after their ends being amputated is a routine method widely used all over the world. However, nobody has ever observed the cut off tail parts being regenerated. Thorough investigations proved that this phenomenon was a result of the animals’ recovery from the malignant tumor. A histological analysis of the regenerated tails’ parts was performed. A histological preparation was made in Professor Sementsov’s Laboratory at Burdenko Military Hospital (in Moscow). The Laboratory comments weren’t preserved but those histological preparations were also studied by K.M. Tantsyura, Assistant Professor at Pathoanatomy Department of Kiev Medical Institute. The expert testified to the fact that “in the referred material the bone regeneration occurred, which passed through the cartilage stage; the shaping of bone beams was observed with the presence of bone marrow cavities filled with marrow”.
The phenomenon of a tail’s end regeneration has also been reproduced in Kyiv Scientific Research Institute of Endocrinology and Metabolism. Its description is shown below.
Description of the experiment on reproducing the phenomenon of an amputated tail’s part regeneration in mice cured of Erlich carcinoma by immunological methods.
In March 1978 Z.P. Uspenska, head of the Laboratory for Cell Protection Mechanisms at the Institute of Molecular Biology attached to the Academy of Science of the UkrSSR, proposed us, O.V.Shevchenko, head of the Laboratory for Experimental Pharmacotherapy at Kyiv Scientific Research Institute of Endocrinology and Metabolism attached to the Ministry of Health of the UkrSSR, M.D.Tronko, academic
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secretary of the same Institute, a senior research worker at the Laboratory for Pathophysiology and G.F. Matvienko, a veterinary physician being in charge of the Vivarium at the same institute, to conduct a check experiment on reproducibility of the phenomenon of an amputated tail’s part regeneration in mice, cured of a solid Erlich carcinoma type. To conduct the experiment an antitumor serum preparation was obtained from the Laboratory for Cell Protection Mechanisms by the Pharmacotherapy Laboratory represented by O.V.Shevchenko.
On 15.03.1978 four non-thoroughbred white female mice weighing 16 to 18gr. were subcutaneously inoculated in the femur area with Erlich carcinoma in the form of 0.2 ml 50% ascitic fluid derived from the mice suffering from an ascitic type of this tumor. The treatment was started 12 days later when tumors of 1x1.5 cm size developed in the mice in the place of inoculation. Antitumor drug was administered subcutaneously of 1.0 ml every second day right up to the total tumor regression (as determined by palpation). The tumors in the experimental animals ceased to be determined by palpation during the interval between the 20th and 30th days since the beginning of the treatment. At the moment, when the tumor tended clearly to diminish, the tails’ parts 1.5 to 2cm long were amputated in those four animals by means of a sharp scalpel. Hemostasis was made by means of a concentrated Kalii permanganas solution.
Over a month’s time the wounds got healed by the secondary intention and covered with epithelium. During the next two months of follow-up an outward appearance of the tails’ stump wasn’t notably changed. The experiment was considered to have failed – a tail regeneration phenomenon was not reproduced. Therefore three of four experimental mice were used for other experiments but one mouse still remained. Soon owing to the force of some circumstances its distal vertebra stripped itself in the place of amputation. Some time later next to the mummified vertebra there appeared a projection that began to extend. By the end of November, i.e. 8 months later after the amputation, the projection took shape of a tail’s regenerate though a bit deformed but with all the signs pertaining to the organ: epithelial scales, mobility and hair.
Thus, a phenomenon of the amputated tail’s part regeneration was fixed by us on one adult mouse, cured of Erlich carcinoma. The picture with the tail‘s regenerate is shown below.
Fig 9. Regeneration of the tail’s end in a mouse cured of Erlich carcinoma by the immunological method
This experiment’s result has one more peculiarity. As is seen from the picture the growth of the regenerate occurred not out of the amputation surface but sideways which resembled the sprouting of a plant branch out of a side bud.
The cured mouse with the irregular tail’s end regeneration was transferred to Moscow for further investigation.
The results of the experiments carried out at Kyiv Scientific Research Institute of Endocrinology and Metabolism were reported to the President of the UkrSSR Academy of Science by the Director of the Institute - Academician V.P. Komisarenko. 2. The phenomenon of lifespan extension in the cured animals
Alongside with the phenomenon of expanding an organism’s regenerative capability in the mice cured of the implanted Erlich carcinoma, a tendency to extend their lifespan was also established (in the average of up to 2.5 years against 1.5 years in a control group).
The implantation of tumor was performed according to the generally accepted methods.
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THE RESULTS OF CLINICAL OBSERVATIONS After the Reversin and antitumor serum atoxicity was
proved by injecting a 10-fold therapeutic dose into intact animals as well as one therapeutic dose into a healthy human (to Z.P. Uspenska) the antitumor treatment by the worked out method was applied to some of the patients of clinical group IV, with a blastomic process at stage IV on request of the patients themselves or their relatives.
The diagnosis of the disease used to be always verified in specialized oncology institutions.
A positive result was established in both female and male patients with malignant tumors of various nature (carcinomas and sarcomas) and diverse localization (mammary gland, genitals, thyroid gland, stomach, esophagus, lungs, testes and others).
Presented below is a very condensed and schematic description of a generalized picture of clinical manifestations in organisms of the patients suffering from malignant tumors to the Reversin and antitumor serum injections. Clinical picture of the treatment process in patients with
generalized malignant tumors On injecting the antitumor Reversin drug into a patient’s
organism there takes place a specific clinical reaction, wherein the following periods can be marked out. Periods of reactions
The period of primary reactions The primary reactions to the Reversin drug’s
subcutaneous or intramuscular injection are of a vascular nature.
Several minutes later hyperemia emerges around the place of injection. Following it the blushing of cheeks, nose, ears, palms and all the visible mucosa as well as that of the nail beds and postoperative scars was generally observed.
Te patient at this time can have caumesthesia on the skin of the face.
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Sometimes there occurred reduction or change in the character of pain sensations if they had been present prior to the treatment start.
Following hyperemia around the point of the skin puncture there emerges a papule of 3 to 15 mm in diameter. It normally disappears 10 to 15 min later while hyperemia may last for some hours more, though directly in the point of a puncture it may last up to several days.
The period of secondary reactions This period is conditioned by the processes proceeding in
the area of tumor nodes’ localization as well as by the general reactions. It is distinguished by a significant polymorphism of symptoms, the presence and expressiveness of which depend on the tumor size, its location and metastases as well as on patient’s state at the moment of the treatment start and the presence of concomitant diseases.
The following symptoms can be observed during this period.
In the setting of normal or somewhat increased body temperature in patients there appears a feeling of “hot flush” or fever (sometimes very high) being localized in the tumor effected areas.
These phenomena are associated with xerostomia and thirst. Sometimes there appears a subjective feeling of a higher temperature in the entire body. Physically the temperature doesn’t exceed 37,5°C.
Specific for the second period are also changes in the pain syndrome.
The nature of pain sensations is generally changed after administering the Reversin drug. Sometimes the decrease in pain or even its complete disappearance occurs. On the contrary the pain can sometimes rise which may be associated with edema occurring periodically and resulting in compression of organs or nerve trunks. Typical of these pains is their periodical nature.
During this period mucosa and skin hypersensitivity to different mechanical, chemical and thermal stimuli can be observed.
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During the recovery period a “creeping” sensation appears periodically in the region of tumor nodes.
If the tumor process was widely spread one could observe a temporary impairment of the patients’ general state in the second period which was likely to be associated with the resolution of necrosis masses that were always present in large tumor nodes.
In this, general weakness, nausea, vomiting, a feeling of rheumatic pain all over the body and constipations alternating with diarrhea can be observed.
In the setting of polymorphism of the symptoms specific to the second period of reaction some cyclic recurrence of their manifestations can be traced.
First (during the first days) they were observed to occur some cycles a day. Then they appeared rarer.
The cyclic reaction may be observed to occur simultaneously in all the tumor effected areas, though it can first cover some zones only, moving on to the others in a due course. The second version of the reaction course is more favourable.
With the favourable progress of the process the above mentioned symptoms’ manifestations go gradually out and then disappear completely. The reaction passes on to the 3rd period - that of the complete recuperation lasting for about a year, typical of which is the absence of any special symptoms not to mention the enormous increase in appetite that turns sometimes into a “gargantuan” appetite (the patient eats up much food, he even dreams about it at night, especially about the forbidden foods). Despite the quality restricted diet the body weight sometimes augments very quickly and can exceed by far the initial weight coming to norm during the following years only.
During a year’s period there occurs complete disappearance of the tumor and its metastases as well as substitution of the tumor-induced defects and also of all the tissues with the corresponding full value tissues in morphological and functional respect (in the liver - by the hepatic tissue, in the lungs – by the pulmonary tissue, in the skin – by the cutaneous tissue, etc.).
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Changes in an organism’s responsiveness during the treatment process
According to the literature data as well as to our observations the responsiveness of patients with expanded tumor lesion is dramatically deteriorated which is shown in the inhibited inflammatory reaction, in particular. Various dermal abscesses disappear, in particular.
A favourable sign testifying to an increase of the responsiveness in a tumor-host (observed normally 2 to 5 weeks later after the beginning of the treatment in most of the patients) was the eruption of abscesses on the entire body (as from a single one to dozens of them). The abscesses soon disappeared.
The patients during this period became hypersensitive to infectious diseases of cold type, in particular. The progression of infection may lead to the reaction “breakdown” which will be commented on later.
Further on with the favourable reaction progress the organism’s responsiveness gets gradually normalized.
In addition, during the patients’ treatment a problem of symptomatic therapy arises. In the course of antitumor treatment the organism’s sensitivity to the whole range of medicines (cardiac glycosides, nitrates etc.) turned out to grow dramatically. The above preparations as administered even in the usual therapeutic doses could cause very severe complications.
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Biological phenomena observed in clinic 1. The phenomenon of curability from malignant tumor
at the generalization stage of the process Clinical observations have established the opportunity for the patients of clinical group IV suffering from malignant tumors at the generalization stage of the process to completely recover which is confirmed by the conclusion of the authoritative medical institutions.
2. The phenomenon of the complete tissular and organotypical regeneration of the tumor- affected organs and tissues After the treatment in the sites of the tumor-affected areas of organs and tissues, a full - value tissue in anatomic and physiologic respects was formed which was confirmed by various investigation methods being applied in clinic.
3. The phenomenon of an organism’s rejuvenescence With some elderly patients cured of malignant tumors, the grey of their hair was observed to disappear; muscles’ strength was observed to augment as well as skin turgor was observed to rise and the working capability to increase, etc.
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The reaction – associated complications
The above described reaction appeared in almost all of the patients in response to the drugs injection. It was more pronounced after the Reversin injection. In case of the serum injection its manifestations were considerably less.
However, not all the attempts to treat people were successful.
In the main, two complications accounted for the failure: • the first one is a too violent progress of the reaction
which was determined by its generalization; • the second one is “a breakdown” of the reaction.
1. Generalization of the reaction With the tumor lesion being extremely massive the
reaction may proceed rapidly and violently. In patients there appeared a state resembling the picture of kinin shock: mental blankness, hemorrhage out of all the mucousa and death.
This complication was observed rarely, it was stated only in two incidents and only after the Reversin injection. 2. “Breakdown“ of the reaction
The most frequent reason for the treatment inefficacy was a complication, entitled as the reaction “breakdown”.
By this term we define a disease course during which positive tendencies in the development of the recovery process terminated allowing the negative ones to occur, that are characteristic of the resumption in the disease process.
After the reaction “breakdown” the tumor growth assumes a progressive character which leads to a patient’s death.
Clinically the “breakdown” of the reaction is determined by disappearance of the symptoms typical of the favourable flow of the reaction and by recurrence of a set of symptoms characteristic of the progressing tumor disease.
The “breakdown” often happened when the patient failed to keep to the diet; it occurred as well without any visible reasons when there was a flaccid (hypoergic) reaction process.
An early laboratory sign of the unfavourable reaction process is a decrease (sometimes dramatic) in the percentage of lymphocytes’ content in peripheral blood.
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After the reaction “breakdown” the character of relationship between the host and the tumor returns to the state similar to one that existed prior to the beginning of the treatment. The similar state is but not the identical one. Testifying to this is the fact that attempts to resume the reaction by the repeated Reversin drug or serum injection failed.
Prevention of the reaction-related complications Prevention of the reaction generalization
In so far as generalization of the reaction was established in the cases of Reversin application only and it was not observed in any other case with serum treatment it is advisable to use serum in case of massive tumor lesion. Prevention of the reaction “breakdown” 1. Prevention of contacts with the infected patients
It is achieved by simple quarantine measures.
2. The use of special diet It was established in the experiments on animals that for
a year following the antitumor drug injection their food should not contain any components of the animal origin.
The inclusion of these kinds of products even in microdoses into the rabbits’ ration during the treatment process led to their death as a result of stimulation of blastomatous process.
In the course of further research a special diet has been worked out. The strict keeping to the diet is compulsory in the treatment of all the experimental animals as well as humans.
In our opinion it was the very factor of failure to keep to the diet that accounted for the reaction “breakdown” in the patients’ treatment. The difficulty in keeping to the diet was that all the patients in all the above cases stayed at home in family surroundings the members of which mostly didn’t alter their traditional way of having meals.
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Indications and contra-indications for applying the new treatment method Indications
Indications to apply the method were worded with regard to the conditions wherein the laboratory employees could have an opportunity to perform the treatment.
Medical indications: the presence of the diagnosis of malignant tumor process
of any nature and localization at stage IV of its development, verified in an official medical institution.
Social and ethic conditions: - refusal by the official medicine to perform the patient’s further pathogenetic treatment (transition to symptomatic one only); - availability of a patient’s consent; - availability of the patient’s relatives consent.
Contra-indications
Absolute medical contra-indication to apply the worked out treatment method is a previous chemotherapy.
Of all the above stated, one can make a conclusion
that the clinical observations carried out, despite the patients’ incomplete clinical examination during the treatment, strongly testify to the antitumoral therapeutic efficacy of both Reversin and antitumor serum.
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METHOD OF MAKING AND APPLICATION OF ANTITUMOR DRUG
“NEOREVERSIN” Being based upon:
• the laborious gleaning and analysis of separate results obtained in the research that took place in 70-ies through 80-ies of the last century;
• the theory of pathogenesis of malignant tumor process created by us,
we tried to reproduce the formula of the Reversin drug and its application technology.
In view of the fact that the original Reversin’s
formula and the method of its application have been lost, we can’t guarantee the identity of the Reversin drug and its application technology with the Neoreversin drug created by us and the method of its application described.
For making of the preparation “Neoreversin” it is
necessary to have two components: extract of placenta and blood of cancer bearing hosts.
Method of making an extract of human placenta The procedure of making a placental extract is carried out
with the greatest observance of aseptic rules. Human placenta is obtained from natural physiological or
artificial cesarean deliveries (the latter is better). The placenta is minced in slices approximately of 2 – 3 sm3 in size (the size of parts has no importance).
The placenta is placed in a sterile vessel. Then there the sterile physiological solution is added in amount 0,5-1,0 parts in relation to placenta weight.
The vessel with placenta is placed in a refrigerator at +20С – +40С for 3–4 days.
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Media (placental extract) is harvested and kept at +20С – +40С not longer than 3 days.
Method of making antitumor preparation
“Neoreversin” and its application to rabbits
Preparation of the animals for treatment by “Neoreversin” This preparation consists only in performance of autohemoterapy once a day during three days. Method of making “Neoreversin” The preparation “Neoreversin” is an active biological
complex which is produced directly before its use (ex tempore).
Preparation of the complex The extract of placenta is taken in a syringe (1,3 – 1,6 ml)
and then in the same syringe the blood of cancer bearing rabbit (0,7 – 0,4 ml) is added. The components are mixed by the air–bead.
This bead is left in the syringe. The mixture is stored in a syringe for 30–40 minutes. The criterion of optimal correlation between the
components is transformations of the mixture in a syringe into gel in an interval of time from 10 to 20 minutes of exposition.
Mode of application of “Neoreversin” The “Neoreversin” is injectied into the rabbit body by
hypodermic or intramuscular injection in amount of 2 – 2,5 ml per one animal.
After the treatment the rabbits should be at complete rest. The diet – exclusively plant food.
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THEORY: A FUNDAMENTALLY NEW VISION
OF ORGANISM'S IMMUNE REACTION IN PATHOGENESIS OF MALIGNANT
TUMORS
Oleksandr V. Shevchenko, Vol. O. Shevchenko, V.O.Shevchenko
SPECIFIC IMMUNE REACTION OF ORGANISM AS INITIATOR AND PROMOTER OF CARCINOGENESIS1
(hypothesis)
Having considered the published data, but devoid of rational explanation in due time, the authors put forward a hypothesis about the decisive role of an organism’s specific immune reaction in pathogenesis of malignant tumor process. The hypothesis was shown not to contradict a contemporary vision of the mechanism of malignant tumor development. It was concluded that the induction in tumor-hosts of immune tolerance to tumor antigens makes retransformation of tumor cells to normal ones possible. Key words: tumors, immune reaction
One of the principal tasks of a theoretical study in any field of knowledge consists in determining that standpoint, from which the object of research could be revealed in the simplest way possible.
D.Gibbs
1 “Journal of Medical Science Academy of Ukraine”, 2004, v.10, №1. – p.50-64 UDC 616-006.04:612.017.1 (Recommended by Corresponding Member of MSA, Ukraine V.A.Mikhnyov)
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The problem of immunologic interrelations between malignant tumors and host is very complicated and intricate. More than a hundred years have passed since the experiment showed the possibility for cancer immune prevention, but the creation of highly efficacious immunologic modes to treat malignant tumors is still waiting for its time to come.
When starting to present our vision on one of the immunological approaches to solving the problem of malignant tumor growth we find it necessary to submit a concise description of its general picture while dwelling at some greater length on those chapters only which are directly associated with the idea asserted in this publication.
As back as the early 20th century S. Jensen published his work wherein he, being based upon the results obtained in the performed research, stated the idea concerning the possibility to artificially create an active immunity to malignant tumors [29]. Soon after, P.Erlich with his colleagues joined in studying this problem [40]. In the fashion analogous to the methods, applied in bacteriology, they immunized animals with avirulent tumor material, developing their resistance to inoculation of already virulent tumors. However, the interest to the research in this area decreased and up to the middle of the last century only isolated reports appeared about the works dedicated to studies of the immunity to tumors. It’s not until the works by E.Foley [28], R.Prehn and J.Main [37], R.Beldwin [21] and others had been published that the researches in the field of tumor immunology were dramatically activated. Using auto- and syngeneic systems, researchers clearly identified the presence of the phenomenon of antitumor immunity. The animals, previously injected with inactivated malignant tumor cells, gained resistance to inoculations with the living tumor material. Almost all the elements (humoral as well as cellular ones) of the immune system were found, and not only in experiments but also in clinic, to be involved in the formation of antitumor immune reaction. However this mechanism doesn’t ensure any protection against malignant tumor growth in natural conditions. This is associated with a number of circumstances. As it has become clear, along with the evolvement of immune reactions having an antitumor
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trend, their blocking mechanisms come into action. Apart from this, there’s one more phenomenon making the situation much more complicated – it is immunostimulation of tumor growth (this phenomenon will be regarded in detail further on). Such interweaving of the processes, having different trends, is apparently responsible for the current state of the immunotherapy, when it is capable of performing, and not always though, a secondary role only. To make sure that it is really so, one can open the last edition of the capital manual on the treatment of malignant tumors “Cancer Medicine” [20]. The following is said there about the possibilities of the immunotherapy: “…favorable results of the immunotherapy can be observed only in patients having microscopic manifestations of the disease provided that the adjuvants were applied after all the clinical tumor manifestations had been eradicated by means of traditional treatment methods”.
Nowadays titanic efforts are being made to boost an organism’s immune reaction to the efficient level by means of antitumor vaccines. A great number of research institutions and firms are engaged in creating them. [19, 26, 27, 31, 32, 41]. However, not all assess unambiguously the prospects of this direction. So, R. Prehn, a lead theorist in the area of antitumor immunity problems, for example, treats it with caution, admitting though the perspective of antitumor vaccination with embryonic tissues [34].
When analyzing pathogenesis of malignant tumors, we paid attention to the phenomenon of malignant transformation of embryonic cells transplanted into ectopic (extrauterine) sites of adult syngeneic animals. This phenomenon has not received any unified theoretical interpretation as yet.
Its exceptionality consists in the fact that embryonic grafts undergo malignant transformation without any carcinogenic impacts, i.e. there takes place carcinogenesis without carcinogens. This fact became the basis for shaping our views as to the role of an organism's immune reaction in carcinogenesis which differed from those generally accepted.
In the late 70-ies and early 80-ies of the 19th century J.Cohnheim’s views concerning the origin of malignant
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neoplasms were shaped [25]. According to J.Cohnheim malignant tumors can be developed either from the remaining embryonic tissues that happened to be among the definitive tissues of the same histogenesis but, due to some reasons, were not involved in the normal tissue building process, or from the embryonic residues, transferred to another site, which appear to become a heterotopic object and therefore are not involved into intratissular interrelations. These embryonic residues give rise to neoplastic growth. In order to prove or disprove this hypothesis the embryonic material (tissues or embryos’ parts) was transplanted into adult animals however there was no growth of tumors from them. But when embryonic cells, isolated from the embryos in pre-implantation period, were implanted into the extrauterine sites of adult syngeneic animals, they were naturally transformed into malignant ones. A well-known expert on the problem of malignant cells’ differentiation, I.Shvemberger spoke on the subject as follows: “The fact that no tumors develop in the case of the ectopic transplantation of definitive tissues allows the ectopic grafts’ malignant transformation from embryonic tissues to be assessed as a particular case of carcinogenesis, that by etiology, pathogenesis and prognosis should be considered individually” [15]. However, the author of the work doesn’t go beyond these recommendations.
In the literature of the following years we haven’t found any attempts to provide this phenomenon with any theoretical interpretation either. Although in our opinion it suggests the existence of some intrinsic cause for transformation of embryonic cells into malignant ones. It is unclear whether this cause can have any relationship to other cases of carcinogenesis. It can’t be excluded that determination of the nature of this intrinsic factor and induction of neoplastic transformation will enable one to find answers to some other questions as to the mechanism of malignant tumors origin.
About 30 years ago G. Svet-Moldavsky [9] explained this phenomenon as follows: in embryos there exist some powerful cellular and humoral factors regulating the embryonic cells capacity to grow and differentiate. They are absent in an adult organism. If embryonic cells are
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reproduced in the organism where there are no factors regulating their growth and differentiation, they’ll become malignant.
In a theoretical study “Embryonic Properties of Tumor Cells: Facts and Hypotheses” Ya. Ehrenpreis [18], touching upon the problem of extrauterine embryonic grafts’ neoplastic transformation, points out, that the reason for it is non-embryonic conditions of such grafts cells’ existence but he doesn’t specify what factor of these conditions exactly is directly responsible for neoplastic transformation. And on the basis of his monograph “Contemporary concepts of tumor growth” [17] only, published in 1987, does it appear that he, like G. Svet-Moldavsky as well, sees the reason for such transformation in the absence of embryonic inductors of differentiation in the adult organism. Such ideas are quite logical. Actually in embryos normally not only does the growth and differentiation of embryo’s own cells occur but so does the differentiation of cancerous cells transplanted into the embryo [30]. However the blank side in these hypotheses is the fact that many attempts to isolate the differentiation factors out of embryos yielded no convincing results. Embryonic extracts, being not infrequently far from inhibiting, have even stimulated neoplasias’ growth.
But rightful can also be another assumption, viz.: in adult organisms there’s a certain factor that induces malignant transformations of embryonic cells which is absent in embryos. What kind of factor can it be? One of the distinctions between embryo and an adult organism is the presence in the latter of the immune-reacting system and its absence in embryos. So, perhaps, the very system itself contributes to the fact that cells, having embryonic properties, become malignant while being transplanted into an adult organism? We are aware of some paradoxical character of such an assumption since usually the effects of an entirely opposite nature are associated with the immune system, as It is the one, which, in compliance with the theory of immune surveillance, resists the development of malignant neoplasms. Nevertheless, it is well known that immune reactions in an organism are being far from playing always a protective role. A lot of examples can be given to show that they are an important and sometimes even a key
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factor in the development of diverse pathologic processes, severe ones included [6].
Let us regard some other arguments speaking in favor of our assumption. Let’s begin with the most principal one. A number of embryonic cellular markers include substances of protein nature with inherent antigenicity in an adult organism in auto- and syngeneic systems. Therefore the embryonic cells that happened to get into the adult organism will be subject to the action of various effectors of the immune system. And this impact will undoubtedly have certain consequences for embryonic cells, that will be manifested if not in their destruction but then in some serious functional disorders, for instance, in differentiation disturbances. Thus the immune reaction seems to be capable of acting as a destabilizer of the situation. We don’t see any other candidates for this role to play.
Let us word this hypothesis as the following postulate: the factor, transforming embryonic ectopic grafts into malignant ones in adult animals in syngeneic system, represents an organism’s specific immune reaction. Let’s consider further on, whether this postulate can be applicable to the cases of carcinogenesis occurring under natural conditions and can be modeled in the experiment, viz.: to blastomas, induced by diverse carcinogenic impacts, as well as to the tumors of viral origin and to spontaneous tumors.
Let us refer again to Ya. Ehrenpreis’ views on carcinogenesis[17]. According to his ideas normal embryonic cells are initially endowed with neoplastic potencies that are realized in the form of malignant growth when embryonic cells happen to get into non-embryonic conditions of their existence; tumor cells are embryonic cells, devoid of the posibility to participate in normal embryogenesis. As for somatic cells, giving rise to tumor growth, they gain embryonic properties and, consequently, also a potency to neoplasia during the latent period of carcinogenesis. Since embryonic properties, in this case, are transferred to cells, not designed for embryogenesis, their further existence is manifested as tumor growth.
If we consider somatic cells, embryonized under the impact of carcinogenic factors, as the particular ectopic embryonic grafts, then the above worded postulate may be
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applicable, in fact, to all of the versions of carcinogenesis. But in that case it seems to come into conflict with oncogene theory, by which the only reason for cells neoplastic transformation is derepression of oncogenes in them and no other conditions for it are required. That is to say the event of oncogenes’ derepression alone is already sufficient for malignant transformation to take place.
To make these discrepancies agree, oncogenes’ functions should be analyzed in detail. Most of the scientists believe that oncogenes play a very important part in an organism (common to all species of living organisms), that of regulating the cells’ growth and their differentiation [4]. Various oncogenes in placental animals are found to be expressed freely in certain periods of their embryonic development and it is quite natural that at this time they are responsible for an organism’s cellular and tissue characteristics, which we call embryonic ones. Oncogenes in the process of an organism’s development are repressed. But if they start functioning in an adult organism, then the products of their activities appear to be immunologically heterologous for the mature organism and a typical immune reaction is developed in respect to them.
Taking into account all the above-stated, the mechanism of malignant process origin is conceived by us as follows. Under the impact of some external or internal factors in organism’s cells there occurs derepression of oncogenes. The direct result of activities of the latter is oncoproteins and other biologically active compounds, embryonic antigens included. In respect to them the organism develops an immune reaction that deforms the vital activity of cells containing activated oncogenes to such an extent, that they lose their capacity for differentiation and get transformed into malignant ones.
This vision of a sequence of events doesn’t deny the oncogene theory, but on the contrary would rather corroborate it as it eliminates the logical difficulty that bewildered many specialists in the field of molecular biology, including such an authority as G. Bishop, who believed that: “What was found in the research, carried out by oncologists, represented the first glimpse behind the veil that had hidden a cancer mechanism for such a long time. What was
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observed, was in one respect distressing since the chemical mechanisms, that apparently “pushed cells off” onto the pathway of malignant growth, did not differ at all from the mechanisms operating in normal cells” (cited by [10]).
We will cite here one more statement. “The oncogene concept, for all its advantages as compared to other concepts of carcinogenesis, has at least one vulnerable link. Scientists tried to understand how the cellular genes being normal and apparently necessary for the vital activity, when undergoing their minimum alteration (and sometimes, maybe, without any but only as a result of their increase in quantity), become detrimental for the cell and the organism as a whole; what sort of genes are they, without which a cell, on the one hand, is unable to exist and, on the other hand, is incapable to resist their harmful action?” [10].
In accordance with the postulate proposed, the problem of this contradiction can be solved in rather a simple way. Actually, the chemical mechanisms (meant here are oncogenes’ products and biochemical functions, brought about by them) operate in a similar way both in tumor cells and in normal embryo cells. No matter whether oncogenes function in embryo cells or in an adult organism’s cells or even in the cellular culture, the result will be identical. There are no reasons to think that their activities’ products can have different properties insofar as oncogenes’ nucleotide matrix remains one and the same in all the cases shown. The whole point is that the organism’s reaction to the derepressed oncogenes’ products in the period of embryogenesis and in the adult state is different. Therefore it is not the chemical mechanisms as such that trigger tumor process but the organism’s immune reaction “pushes” the cell, embryonized as a result of oncogenes’ disinhibition, off the normal pathway of differentiation.
In this connection it is necessary to consider a well studied phenomenon – the phenomenon of immunostimulation of tumor growth, playing an important role in pathogenesis of malignant tumors. However, today it hasn’t yet been given due attention either. This phenomenon was identified when studying the immune reactions’ impact upon the tumor process. Its manifestations were unnatural and unclear. The reason for immunostimulation was first
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believed to be some factor, not yet explored, that was even termed as XYZ to emphasize its enigmatic nature. However it was revealed very soon that this factor’s nature doesn’t differ at all from the already known immune reactions.
The facts about the tumors’ immunostimulation have been accumulated and finally an attempt has been made to theoretically construe them. The tumor growth was believed to be enhanced due to the blocking factors that impaired the antitumor action of immune reactants and the tumor cells started to reveal more freely their potential to rapid and unlimited growth. But such a view was radically changed on the boundary between 60ies-70ies, after R. Prehn started working on this subject. At first the results of his experimental works were published followed then by a fundamental theoretical study carried out by him together with M. Lappe [36]. This work showed that it was the direct action of immune system reagents that led to the stimulation of tumor growth. This kind of effect is induced by the impaired immune reaction while the strong one is responsible for the inhibition of tumor growth. Some time later, a series of experimental and theoretical works by R. Prehn and other researchers appeared to add arguments in favor of the theory of tumor growth immunostimulation.
The opposite trends of the weak and strong immune reactions’ action upon tumors isn’t something extraordinary. It represents a well-known regularity consisting in that the small doses of biologically active agents (even toxic ones) stimulate the functions of biological systems while the large ones – inhibit them. A great number of examples can be given to confirm the universality of this principle. Therefore the immune action on tumor cells isn’t an exception. The action of the weak immune reaction upon a tumor will be that of stimulation but with its power being increased the stimulation terminates and the inhibition starts. The arrival of this moment depends on the “stimulation width” (let’s thus term it) of the immune action, i.e., on the range between the power of immune reaction, when the stimulation just begins, and its level when the stimulation is over. In pharmacology corresponding to this notion is “therapeutic range” of drugs’ dosage.
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Based upon observations of the tumor growth in diverse versions of the experiment, R. Prehn has worded a postulate by which every tumor in order to be stimulated requires the immune reaction of such a magnitude and character, that is peculiar to it alone [35].
Insofar as the specific immune reaction to the tumor arises and develops gradually, its power will be first small – the stimulation of tumor growth will be observed. Then, despite the increase in this power, the blocking mechanisms (aforementioned) start operating which will restrain this augmentation. Integrated power of the immune reaction in reality doesn’t ever reach magnitudes at which tumor destruction starts. It remains always weak and acts as a stimulator of tumor growth.
In the early 80-ies of the 20th century A. Ageenko and co-authors performed a series of works, the results of which are fundamentally important in terms of our knowledge of the immune reaction role in pathogenesis of malignant tumor growth. The authors put forward their own concept of the role the immune system plays in pathogenesis of malignant tumor growth, the underlying idea of which implies the particular importance of embryonic antigens in the processes of tumors’ origin and progression [1]. On the surface of transformed cells at least two antigen groups were shown to be expressed that mediate a different qualitative result of immunologic interaction between tumors and lymphocytes – immunocytolysis and immunostimulation. The latter significantly exceeds immunocytolysisis in its power and is realized in the line of stage-specific embryonic antigens. The authors arrive at the opinion by which “it can’t be excluded that immunostimulation is the mechanism that triggers carcinogenesis and might afterwards play an essential role in tumors’ progression”[1]. Thus these investigations proved that an organism’s immune reaction to the transformed cells plays an important role.
We consider it necessary to make here a short digression in order to introduce an extraordinary essential specification. We use the definition of “embryonic antigens” in relation to those substances only, that being typical of embryos at the early stage of ontogenesis, start to be expressed on plasmatic membranes of transformed (i.e. embryonized)
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cells and are immunogenic in autochthonous hosts and syngeneic systems, and also activate T-lymphocytes. It is important to emphasize this as the term “embryonic antigens” is used widely enough in relation to a number of substances that don’t generate any immune reaction in hosts nor do they activate T-lymphocytes. These are, for example, α-fetoprotein and carcinoembryonic antigen that aren’t actually the specific markers of tumor process, but the markers of proliferation alone. The importance of this circumstance was emphasized by J. Coggin [22], who indicated two antigens, in particular, which were expressed in embryos and malignant tumors only and couldn’t be identified in any other normal tissues by means of the most high-sensitive technique. These are glycoproteins with molecular masses of 44 and 220 kDa.
The fact, that such embryonic antigens have been identified in all the tumors studied, without regard to the source of their origin (ecto-, endo- or mesodermal) and a species-specific belonging of the hosts (human, rodents) [22-24,39] suggests the presence of universal features in malignant tumors. If we take into account this circumstance and an extraordinary limited quantity of these features, then, finding the method to appropriately affect them, would make it possible to work out a unified approach to malignant tumors’ treatment.
Returning to the main subject of our study, we may state that an organism’s specific immune reaction in respect to malignant tumors is protective only in theory. In reality, it is one of the initiating factors of neoplastic process and its promoter.
Proceeding from the stated ideas on the mechanism of neoplastic process formation and development, malignant tumors should be interpreted as autoimmune pathology. Richmond and Lisa Prehn in their article “Autoimmune Nature of Cancer” [38] wrote the following: “Since the immune reaction facilitates oncogenesis by MCA, MCA-induced cancer can legitimately be termed an autoimmune disease”. In this, the authors consider the MCA system isn’t likely to be a unique one. Therefore they believe that when it becomes known how to prevent autoimmune diseases, it will be possible just as well to prevent not only the development
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of MCA-induced cancer, but also the majority of malignant tumors. A. Ageenko and V. Yerkhov single out an autoimmune constituent of carcinogenesis too [1].
We, as distinguished from the many researchers mentioned, believe that the immune system not just stimulates the neoplastic growth, but we also substantiate the statement, that it is a malignisative factor for cells, expressing embryonic antigens; that it is the immune system that plays a key role in the mechanism of malignant process formation and development. The significance of diverse carcinogenic effects comes thus to their capability to derepress oncogenes at that time, when a highly powerful system of non acceptance for their products has been already formed, namely, the immune system. It provides more grounds to speak of the malignant tumors as a variety of autoimmune diseases.
Let’s now have a look at the other versions of carcinogenesis and the experimental schemes to fight the tumor growth in light of our postulate. Let’s dwell at first upon the general theory of cancer by A. Cherezov [13] according to which the reason for malignant tumors origin lies in the tissue homeostasis’ disturbance. In correspondence to the author’s ideas the structure of tissue homeostasis consists of the various tissues’ stem (cambial) cells having a high proliferation potential as well as all the signs of embryonality (autocrine stimulation of mitoses, unrepressed oncogenes). These cells ensure the renewal of the bulk of tissues’ specific cellular elements that gets diminished as a result of natural deterioration and destruction. The strictly measured functioning of stem cells, which corresponds to the scopes of natural losses in the deteriorated differentiated cells, is ensured by the mature cells’ capability to produce substances, (chalones), having the property to inhibit the cambial cells’ proliferative impulse. Under the action of various carcinogenic substances there occurs disarrangement of feedback mechanisms and the cells’ proliferation process begins to prevail. Many young cells that have no time to differentiate are accumulated in tissue and there occurs the tissue embryonization. As a result, the tissue homeostasis structure and also then its function are destroyed and a tumor originates. But it remains unclear
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when the moment comes for the accumulated aggregate of young embryonized cells to cease being the normal tissue and to be transformed into a malignant one. We don’t find any answer to this given by the author of the research. If viewed from the standpoint of the postulate under consideration we will see the answer to it lying right on the surface. The embryonization process of proliferating tissue won’t go beyond the frame of the normal phenomenon until a certain amount of stem cells that are being reproduced and express embryonic antigens, reaches the critical mass, capable of becoming an object of reception by an organism’s immune system.
Immunologic recognition is known to take place only in that case when the cells, bearing heterologous antigens, make up a group of no less than 105 units [5], while the tissular conditions don’t impede it. The immune reaction that follows, imparts a malignant phenotype to the cells. It is this very moment that is crucial in the origin of neoplasms in all the versions of tissue homeostasis’ disturbances.
Proceeding on with the discussion of the postulate, let us refer to the classic experiments conducted by B. Mintz to obtain allophenic chimeras [30]. The allophenic chimerism of healthy and full-value animals emerged in these experiments as a result of inoculating into the blastocyst of mice of one line the teratocarcinoma cells, derived from the animals of another line which had clear-cut phenotype distinctions from the first one in the form of black fur coloring as well as some biochemical markers. In the mice produced from the blastocyst with the inoculated malignant tumor cells, the tissues and organs (right up to germinal ones) were built of the maternal organism cells and of the inoculated malignant tumor cells that lost their malignant phenotype and were involved in normal embryogenesis.
Teratocarcinomas are known to be obtained by inoculating the embryonic cells of an embryo of pre-implantation stages of its development into the so called immunologically preferential sites (anterior chamber of the eye, testes, subcapsular space of the kidney and others), wherein there are conditions of relative immunological tolerance. Manifestations of the immune reaction can be observed in these sites too though in an impaired form [15].
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This immune reaction appears to be sufficient to impart malignant phenotype features to the inoculated embryo cells. Further on, these cells (being already malignant ones) are passaged on mice in the form of ascitic teratocarcinoma, i.e., they are always placed in non-embryonic conditions where they are recognized by the immune system and are perceived by it as foreign ones. Before being used by B. Mintz in her experiments such teratocarcinoma cells have previously gone through 200 passages in the form of a malignant phenotype. But once they happened to get under the conditions of a developing embryo they immediately lost their malignancy. This suggests the fact that a malignancy sign in this case is not associated with the stable genic aberrations, but is shaped by the environmental conditions where the main point is the presence or absence of an organism’s immune reaction. Consequently, the embryo cells being exposed to an organism’s immune reaction are transformed into malignant ones, while the malignant cells, when getting under the conditions of normal embryogenesis (with no immune reaction present), become normal and capable of being involved into the normal form-building process.
In the midst of the 70-ies of the 20th century in the Institute for Oncology Problems Acad. Sci. UkrSSR, investigations were carried out, the results of which were consonant with the experimental data, described by B. Mintz. When cultivating in diffusion chambers under the conditions of a healthy animals’ organism the Shwets erythromyelosis cells of rats, featured by non-differentiated blast elements of myeloid and erythroid series, M. Baranovsky [3] observed their differentiation, that over 13 days’ period of explantation in the red branch of hemopoiesis was completed with the appearance of nuclear baso-, polychromato- and oxyphile erythroblasts, but in myeloid- monocytic branch of hemopoiesis – with the appearance of final functional (phagocyting macrophages) and morphologic (segmented granulocytes) forms. Thus, suffice was it to place leukemic cells, by means of a diffusion chamber under the conditions of isolation from the organism’s immune system (it being represented by its cellular elements only) that their differentiation started to
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occur. However the results of these experiments have never been analyzed in this aspect.
It will be expedient to mention here the findings of several studies that obtained evidences to the effect that malignant tumor cells, being inoculated into embryo, don’t give rise to neoplastic process. So, taking into consideration a generally known fact of the absence of spontaneous tumors in higher animals at early stages of embryonic development, A. Savinska [8] cleared up the question as to whether implanted tumors would grow and develop in embryos in different periods of their intrauterine development. Sarcoma cells’ suspension N16 in physiological solution or Ringer solution with carmine, added for control, was injected through the uterus wall into rats’ embryos. 282 rats (2204 embryos) were operated. 172 embryos (36 rats) were brought to the end of the experiment. Sarcoma, inoculated into embryos at the last third of their intrauterine development, grew and developed both in newborn rats and in female-mothers. When inoculating sarcoma to embryos at the first two thirds of their intrauterine development, tumors were developed in females only. The newborn little rats remained entirely healthy. The tumor failed to have taken on in anybody out of 19 embryos at this period of intrauterine development. Origination of tumors in all the cases of pregnant females after inoculating the tumor material into embryos suggests that the material was living and virulent. A.Savinska’s experiments were repeated by M. Whisson [42] with implanted Iosid sarcoma of rats – no tumors emerged in anyone of 72 embryos that had undergone operation.
Similar experiments were also conducted by B. Tokin and M. Aizupet [12]. Jensen sarcoma cells’ emulsion was injected into rats’ embryos (from 9 to 12 days of pregnancy). Little rats at the age of one week and adult animals served for control. Out of 172 fetuses born who were inoculated with tumor suspension in the period of their embryonic development, only 11 (6,4%) developed tumors. In control animals tumors have been taken on in 80% of cases.
Tumors’ non-inoculability in embryos of the first two thirds of pregnancy in experiments, conducted by A. Savinska, M. Whisson and B. Tokin, can be easily explained from the standpoint of our postulate, that is, by undeveloped immune
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system in embryos and, therefore, by the absence of its action upon tumor cells.
The degree of success of malignant tumors implantation into embryos of both young and adult animals coincides in terms with the stages of formation of their immune system. Unfortunately, the state of the inoculated tumor material was not studied further on in the above experiments.
Thus the main stages of carcinogenesis, in our opinion,
may be considered as follows: 1. The initial material for malignant neoplasms is cells,
expressing embryonic antigens. 2. Such cells might emerge in an organism either as a
result of oncogenes’ disinhibition under the impact of various carcinogenic factors or as a consequence of tissue homeostasis’ disturbances, during which the disturbance in balance between cells’ proliferation and differentiation occurs with the predominance of the first one. In case of a long-term character of proliferation process and increase in the imbalance mentioned, there may be a local accumulation of a significant amount of young (stem, committed) cells having embryonic characteristics.
3. Such cells, according to the existing views [5], are exposed to the effectors of an organism’s natural resistance system, capable of recognizing small amounts of aberrant cells, right up to the isolated ones. A considerable number of these cells may be destroyed but some amount of them is preserved evading cytolysis.
4. The next stage in the development of tumor process is the formation of a cellular conglomerate out of the cells, having survived after the “attack” of the organism’s natural resistance system, of no less than 105 cells — a critical mass that can be recognized by the receptors of a specific immune reacting system.
5. After the immune reception of antigenic determinants of accumulated cells’ has occurred the stage of formation of an organism’s immune reaction to those determinants its action upon the cells which finally calls forth their malignant transformation.
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6. Since this moment an antagonistic interaction originates between the organism and tumor cells, that is manifested in the form of tumor disease with all the variety of symptoms, during which progressive tumor growth is continuously supported by the immune stimuli. Malignancy of the neoplastic process flow depends, on
one hand, on how strong are the tumor cells’ potencies for the progressive growth (as a rule, the less differentiated are the cells, the higher are these potencies); on the other hand it depends on how the character and the power of an organism’s immune reaction in respect to the tumor correspond to that level of this reaction at which its strongest tumor-stimulating effect is observed.
Summing up all the above-stated we come to the following conclusion: irrespective of the nature and kind of carcinogenic factors as well as the circumstances of their action, a cellular conglomerate expressing embryonic antigens is shaped in an organism, sufficient in quantity for its reception by the organism’s immune system. It is the impact of the immune system effectors upon this conglomerate that is responsible for its gaining the properties of a malignant tumor and for a further promotion of its growth.
Thus, the specific organism’s immune reaction is unable to realize that kind of action, on which so much hope was once set. Under the natural conditions, it realizes just the opposite function, bringing about the formation of a malignant tumor process and promoting its development.
Contemporary oncology has two alternative directions to solve the problem of malignant tumor growth. Both the first and the second ones are science-based and have a perspective for achieving favorable results. The main idea of the first one consists in striving to radically eliminate tumor cells wherever they may be [7]. Nowadays tremendous intellectual and material resources are turned to the development of this direction. Another direction is based on the data, according to which malignant tumor cells retain their potential capacity for differentiation [11, 15, 33]; it provides for the possibility to create conditions for retransformation of malignant cells into normal ones (it’s in an ideal case) or to achieve partial rise in the grade of tumor
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cells’ differentiation, resulting in their malignancy decrease [14]. Advantages and attractiveness of such a direction are indisputable. It is this second pathway where we see the prospects for our ideas to be developed.
We believe that the transformed cells’ capacity for differentiation may be realized, on condition, that the factor impeding it, i.e., an organism’s immune reaction to tumor antigens, the embryonic ones in particular, has been eliminated.
Analyzing the problem of malignant tumor growth under some other aspect, M.G. Baramiya arrived at the similar conclusion: to overcome the disintegrated (i.e. malignant) growth it’s necessary to induce and maintain in a tumor-host a status of absolute immunologic unresponsiveness to the transformed phenotype [2].
We regard all the above-stated as substantiation of a fundamentally novel immunological approach to malignant tumors’ treatment, and the previous experimental findings corroborate the productivity of this idea [16].
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8. Savinskaya A.P. Implantability of tumors in various periods of an animal’s individual development // Trudy AMN SSSR. 1952. – 9. – P.323-333.
9. Svyet-Moldavsky G.Ya. Issues of tumor immunology // Immunologiya opukholei. – Kiev: Naukova Dumka, 1975. – P.222–224
10. Seitz I.F., Knyazev P.G. Molecular oncology. – L: Medytsyna, 1986. – 351 p.
11. Timofeevsky A.D. Experience of cultivating rabdomiosarcomas. On the problem of malignant tumor cells’ capacity for differentiation // Vrachebnoye delo. – 938. – №8. – P.569–576.
12. Tokin B.P., Aizupet M.P. About inoculation of sarcoma into embryos //DAN SSSR 1940. – 29. – P.634-636.
13. Cherezov A.E. General theory of cancer. Tissue approach. – M.: Izdatelstvo MGU, 1997. – 356 p.
14. Chekhun V.F. Pharmacocorrection of differentiation and apoptosis of cells in malignant process // Zhurnal AMN Ukrainy. – 1999. – 5. – №3. – P.442–452.
15. Shvemberger I.N. Normalization of tumor cells. – L: Nauka, 1987. – 139 p.
16. Shevchenko Vl. A. Shevchenko A.V., Shevchenko V.A. The problem of malignant tumor growth. A fundamentally new solution. – http:// www.cancercure.kiev.ua.
17. Ehrenpreis Ya.G. Modern concepts of tumor growth. – Riga, "Zinatne", 1987. – 120 p.
18. Ehrenpreis Ya.G. Embryonic properties of tumor cells: facts and hypotheses. // Experimentalnaya onkologiya. – 1982. – №6. – P.13–18.
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24. Coggin J.H.Jr, Barsoum A.L., Rohrer J. W. 37 kiloDalton oncofetal antigen protein and immature lamining receptor protein are identical, universal T-cell inducing immunogens on primary rodent and human cancer // Anticancer Res. – 1999. – 19. – P.5535–5542.
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Discussion The results of the experimental and preceding clinical
studies described may be regarded as a confirmation of the productivity of our hypothesis’, main postulate according to which the way to fight malignant tumor process lies via elimination in a tumor-host of the immune reaction to tumor antigens, but in that case only if to consider that the injection of placenta extract into an organism of patients suffering from malignant tumors induces in it immunologic tolerance to these antigens. The findings of other researchers give ground to consider it so.
In 1980 G.Chaouat and colleagues [1] reported that using the water placenta extract of mice at the second week of pregnancy they induced in these animals a state of immunologic tolerance to alloantigens which was manifested by the allograft having been taken on in them.
In this, two conditions were determined under which this phenomenon could be realized: a recipient of the graft must have a previous contact with alloantigen while the allograft cells must be injected into the recipient together with placental extract or in a very close vicinity to each other.
In 1983 the results of studies by T.Mekori and R.Kinsky were published [8], who keeping to the fundamental scheme of experiments conducted by G.Chaouat induced in mice the tolerance to xenoantigens (erythrocytes of sheep and pigeons). Placenta extract was prepared according to the methods described by G.Chaouat. The researchers also confirmed the necessity for the animals to have a previous contact with antigens to which the tolerance is to be induced and a previous contact of placental extract with these antigens. The placenta extract without the previous interaction with the antigen caused no suppressive effect. The induced tolerance had a specific character which was demonstrated by modulating the crossed reactions with sheep’s and pigeons’ erythrocytes. The following scheme for the immunosuppressive action of placental factor can be drawn out. It is being produced in an inactive form, gaining its potency and a specific character on having a contact with antigen. Being activated it manifests its immunosuppressive effect under the only condition, that of getting sensitized by
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the identical antigen of the organism wherein immunologic tolerance is being induced.
Some time later G.Chaouat and his fellow-workers found out that a similar immunosuppressive factor can be also produced by human placenta [9].
Thorough studies of the impact of placenta immuno-regulatory factors upon diverse indicators of the state and responsiveness of an organism’s immune system [7,11] found out that the immunosuppressive effect of placental extracts is conditioned by a number of compounds with a molecular weight of 5 through 200 kDa. They inhibit natural killers’ activity and also cause a profound dose-related inhibition of an activated T-lymphocytes’ response to the action of antigen. There are various ideas as to whether this inhibition is a result of an activated T-cells clonal deletion or of their anergy. In one of the last works dedicated to this issue G.Chaouat and al. are prone to think that the reason for the inhibition is not the deletion but the anergy of T-lymphocytes [6].
When the comparing of the methods of making placental extracts and their application, which G.Chaouat and his collaborators used, with our method, we have revealed their full basic analogy.
Namely, in both cases: • salt solutions are used for extraction of the active
factor of placenta; • the body into which the placental extract is injected,
was sensibilized with corresponding antigens (in our case – with tumor antigens);
• the extracted placental factor before its injection into the body had contact with an antigen, to which the tolerance was induced (in our case it was a tumor antigen contained in tumor-bearing′ blood).
The comparison made allows one to think that the injection of placenta extract into tumor-hosts induced in them the state of immunologic tolerance to tumor antigens and it was exactly that very factor which triggered the reversion of malignant tumor process.
Now let’s briefly review and analyze the phenomena observed in carrying out the research described above.
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The phenomenon of reversion of malignant tumor process
It is undoubtedly the principal one. Our vision of the reasons and the mechanism of its emergence is stated above in the sections “Theory” and “Discussion”.
The phenomenon of gaining by the blood serum of
rabbits, cured of Brown-Pearce carcinoma, the therapeutic antitumor properties
We consider it to be the second important one. We know nothing about the factor being responsible for these properties to appear besides the fact of its existence. Nor do we know about its physical or chemical features. However, as we’ll see further on, it is the most perspective in terms of introduction into practical medicine. This factor obviously, just like also Reversin, induces in a tumor-host a state of immunologic tolerance to tumor antigens. Speaking in favour of this is a similar clinical picture of recovery in patients suffering from malignant tumors and the appearance of accompanying phenomena (for example, rejuvenescence).
The phenomenon of a sufficient Reversin’s single
therapeutic action It has its own feature consisting in that the therapeutic
composition may be administered both parenterally (subcutaneously or intramuscularly) and as applications onto the mucousa (for example, groin). As to the mechanism of the Reversin’s action there appear some reflections. It’s hard to imagine that the injected placental factor being activated by tumor antigens will be preserved long in an organism and will be acting over a long period of time. It is evident that the factor after having acted by itself triggers the mechanism for supporting the state of the organism’s tolerance to tumor antigens. What kind of mechanism is this, how long can it act, what are the conditions necessary for it to function, what is its breaking mechanism (we’ve mentioned about such a phenomenon afore) and how to eliminate all those failures? All these questions can only be answered by further studies in this direction.
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The phenomenon of universality of the tolerance inductors action
It consists in that these inductors (Reversin and serum) cause therapeutic effect irrespective of tumors type or their localization and regardless the biological species of tumor-hosts. It may suggest one thing only that in all the cases of the development of malignant tumor process there is a common determinative central link which was acted upon exactly in the above described research. And this link, as was proved by our theoretical study, is an organism’s immune reaction to tumor antigens. It can’t be excluded that a key position in this link is occupied by the antigens identified and described by J.H.Jr. Coggin and his colleagues [2,3]. If this fact is corroborated then the alluring prospects will be opened to develop the universal efficacious antitumor drugs of the Reversin type.
The phenomenon of species-nonspecific action of a
suppressor factor (or factors) derived from placenta and blood serum of tumor convalescents
This phenomenon was manifested in that in all the cases of treating both rabbits and humans as well as horses a sole human placenta extract was used. The blood serum of cured rabbits caused a therapeutic effect both in mice and in humans and in rabbits as well. This phenomenon was fixed also by G.Chaouat with colleagues in his research [9] who observed immunosuppressive action of the factor, derived from human placenta, in mice.
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The phenomenon of malignant tumor regression in the setting of a sharp increase in its vascularization
In our opinion it is an important discovery of the entirely new phenomenon. This phenomenon is described by us and is documented by a series of photos (see the text). Up to now it has been regarded (and there are good reasons for it) that the condition for malignant tumor regression is the restriction of its blood supply while in this case we have observed quite the opposite picture which suggests the presence in an organism of an active mechanism for fighting the malignant tumor process that requires an increased blood inflow for it to function. In section 2 of the book when describing the clinical observations we pointed out that in the setting of a normal or somewhat higher body temperature in Reversin-treated patients there appears a heat sensation in tumor-affected sites. It may be admitted that in these sites a tumor vascularization occurred similar to that observed in rabbits on the eyeballs. The mechanism of this phenomenon undoubtedly deserves to be profoundly studied.
The phenomenon of rejuvenescence of tumor
convalescents If to consider that a key moment in a cell’s neoplastic
transformation is its embryonization as a results of oncongenes’ desinhibition then the described rejuvenescence phenomenon can be explained as follows.
A mass of young ebryonized (transformed) tumor cells, as a result of being no longer subject to the action of the immune system reactants, turns into a kind of embryonic autoimplant to become a powerful source of rejuvenating influence onto the entire body. The recent research performed [4,5] found out the presence in young organisms of an unidentified as yet rejuvenating factor, by means of which the authors of the work succeeded in restoring the potency for regeneration of the aged animals’ muscles to the level of young ones. This factor exerted the same effect also upon the liver. It’s logical to assume that the younger are the tissues the more of this factor will they contain. It might be that in our case also the convalescents’ rejuvenescence occurred due to this factor.
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It should be noted that while after treating horses they (all of the three ones) were observed to have their organism rejuvenated, in oncology patients that had a successful treatment the rejuvenescence phenomenon was far from being observed always to occur. As for its reasons, there may be some assumptions made. One can’t exclude the dependence of the rejuvenescence phenomenon manifestation from the tumor mass. This effect was observed, for instance, in a woman-patient with genitals heavily affected with tumor, as well as in a patient with two-sided lungs carcinoma. There may be also the relation between the manifestation of the phenomenon and the degree of tumor cells differentiation. The less differentiated are these cells the stronger their rejuvenating effect can be expected.
The phenomenon of expanded regenerative abilities
of an organism cured with antitumor serum from the implanted malignant tumor
This phenomenon was manifested in a full-value regeneration of the amputated tails’ ends in mice with all the structural features preserved: vertebrae, skin integument, pelage and mobility. As is suggested by the literature data [10] such kind of regeneration in those animals can be possible only in the period of their embryonal development. And the fact of it being manifested in adult individuals can suggest that their organism’s rejuvenescence occurred onto a very deep level.
The phenomenon of the tumor cells retransformation
into normal ones As is fixed on the photos №1 and №2 of the kidneys and
the liver of a rabbit slaughtered at the intermediate treatment stage, in the center of metastases the zones of hemopoiesis are observed to appear (dark spots). And in the liver (photo №2) in the center of a metastasis which is being resolved and to a lesser degree in other ones, a pattern of the liver normalized structure can be seen.
Such a picture is regarded by us as manifestation of tumor cells’ retransformation into the normal ones.
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The mechanism of emergence of this phenomenon is seen by us as follows. The cells wherein the derepression of oncogenes occurs, after being returned as a result into the embryonic state, acquire the corresponding properties, pluripotency in particular. But these cells are prevented from realizing these properties by an organism’s immune reaction. By eliminating the latter this will be made possible. The direction of differentiation for embryonized cells will be defined by the signals from the microenvironment of tumor and its metastases.
Such a vision of the process allows the assumption to be made that metastases imported for instance into the lungs or kidneys, will be differentiated into the young cells of these organs correspondingly.
Histological tests performed by a fellow - worker of the Laboratory, V.Rachinsky provide all the grounds for such an assumption to be made. As was indicated by Academician A.P.Avtsyn on getting familiarized with the study results, this assumption has the right for existence but it still requires to be corroborated with some weighty arguments.
The phenomenon of post-convalescent antitumor
resistibility The essence of the phenomenon consists in that the
rabbits cured of Brown-Pearce carcinoma by means of Reversin couldn’t repeatedly take on this carcinoma.
The phenomenon of a lifespan extension in the
animals cured During the follow up of the cured animals a tendency to
extend their lifespan was marked. However this issue needs more large-scale and long-term research to be conducted.
The phenomenon of changing the external phenotype
signs (hair-coat coloring) in a female rabbit cured of Brown-Pearce carcinoma during the period of her progeny reproduction
This phenomenon is very interesting as it is. It is documented by a series of successive photos. However nothing exactly can be currently reported concerning the mechanism of its emergence.
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References to Discussion 1. Chaouat G., Chaffaux S., Duchet-Suchaux M. and Voisin Y.A. Immunoactive products of mouse placenta. 1. Immunosuppressive effects of crude and water soluble extracts. F.Reprod. Immunol. 1980; 2. P.127–139. 2. Coggin J.H.Jr. Classification of tumor-associated antigens in rodents and humans. Immunology Today. 1994. 15. P.246–247. 3. Coggin J.H.Jr, Barsoum A.L., Rohrer J.W. 37 kiloDalton oncofetal antigen protein and immature lamining receptor protein are identical, universal T-cell inducing immunogens on primary rodent and human cancer. Anticancer Res. 1999; 19. P.5535–5542. 4. Conboy I.M., Conboy M.J., Smythe G.M., Rando T.A. Notch-mediated restoration of regenerative potential to aged muscle. Science, 2003; v.302, № 5650. P.1575–1577. 5. Conboy I.M., Conboy M.J., Wagers A.J., Girma E.R., Weissman I.L., Rando T.A. Rejuvenescence of aged progenitor cells by exposure to a young systemic environment. Nature, 2005; v.433, P.760–764. 6. De Smedt D., Menu E., Chaouat G. Immunoactive products of placenta. VI. Induction of transient murine T-cell anergy by low–molecular–weight compound obtained from supernatants of human placental cultures. Cell.Immunol. 1997; 175. P.128–140. 7. Djian V., Menu E., Thiboult G., Roperi S., Chaouat G. Immunoactive products of placenta. V. Immunoregulatory properties of a low–molecular–weight compound obtained from human placenta cultures. Am. J. Reprod. Immunol. 1996; 36. P.11–24. 8. Mekori T., Kinsky R. The ability of placental extracts to modulate a direct PFC reaction to a SRBCs in mice. Immunol. Letters. 1983; 6. P.21–24. 9. Menu E., Kaplan L., Andreu G., Denver L., Chaouat G. Immunoactive products of human placenta. I. An Immunoregulatory factor obtained from explant cultures of human placenta inhibits CTL generation and cytotoxic effector activity. Cell.Immunol. 1989; 119. P.341–352. 10. Mitskevich M.S. Regeneration and ontogenesis. Regeneration process in mice’s embryos. Biologicheski jurnal. 1934; v.III, № 1. P.20–27. 11. Raghupathy R., Khan S.F.B., Syamasundar P.V., Azizen F. A placenta-derived suppressor factor with a T-cell bias. Am. J. Reprod. Immunol. 1999; 42. P.205–218.
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GENERAL CONCLUSIONS
The achievements of the work described in the manuscript are considered by us to be as follows:
1. Discovery of a new phenomenon – the induced
reversion of malignant tumor process and the whole range of accompanying biological phenomena, most of which were identified and described for the first time.
2. Elaboration of a theory that:
• essentially supplements the existing notions about pathogenesis of malignant tumor process;
• explains the reasons for the emergence of the phenomenon of a malignant tumor process reversion as well as the number of biological phenomena described in the book;
• substantiates another approach, being a fundamentally new one, to the malignant tumors’ treatment.
3. The development of a fundamentally new immunological method to treat malignant tumor process.
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THE PROSPECTS OF IMPLEMENTATION The reality of a perspective to adopt the new efficacious
method substantiated in the monograph, for malignant tumors’ treatment into medical practice will justify all the future financial and organization expenses, associated with it.
This implementation in our opinion should consist of a number of stages.
The first stage
The broadest possible familiarization of the world scientific public with the materials of the given elaboration
The authors are prepared to answer all the questions that can arise in the parties concerned as to the details of the experiments performed, the production of therapeutic preparations and their application.
The second stage
Conducting the check researches To seriously raise the question about the implementation,
it’s necessary to have a confirmation of reproducibility of the proposed method to fight the malignant tumor process.
The check research should be performed in keeping to the strict conditions of objectification and by an authoritative scientific institution that could make a highly qualified conclusion as to the efficacy of the method. Such a conclusion alone can be the basis for further actions.
Insofar as the method‘s efficiency was the most illustratively displayed on the model of implanted Brown-Pearce carcinoma in rabbits we advise when conducting the check experiment to use this model in the first place.
The study of the proposed method’s efficacy in malignant tumors’ treatment may be also conducted on horses.
In case the results to be obtained are sufficient for making a positive conclusion a question will arise as to further actions.
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The third stage Creation of antitumor pharmacological
preparations and development of its application techniques
As appears from the studies described above two versions of antitumor drugs may be developed.
1. Creation of the Reversin-type drug. 2. Production of antitumor serum. The shortest way to its implementation is the creation of a
serum preparation. And that is why. Neoreversin is a two-component drug. Therefore both of
its components should be worked through. Each of them is associated with significant difficulties in terms of standardization. Much simpler is to produce antitumor serum.
Antitumor properties of the animals’ blood serum appear after they have been cured from a malignant tumor by means of Reversin. To estimate the serum antitumor efficacy the experimental models of implanted malignant tumors can be used. (We used the model of a solid Erlich carcinoma in mice). Thus, one can avoid the difficulties associated with non-standard Neoreversin components.
The following general scheme can be drawn out to obtain the serum preparation.
A group of rabbits is formed to be implanted with Brown-Pearce carcinoma being afterwards cured by means of Neoreversin. These rabbits become donors of serum. The latter is standardized on mice with an implanted tumor.
The opportunity should be also studied to obtain antitumor serum from the horses cured of melanoblastosis by means of Neoreversin.
Simultaneous researches can be carried out as to the standardization of Neoreversin components.
The key and rather complicated problems of this research are as follows:
• Study of a placenta suppressor factor and the prospects for its synthesis; • Study the opportunity to use embryonic antigens as a universal standard component of Neoreversin.
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APPEAL Dear colleagues,
In the book, presented for your attention, we have theoretically substantiated a fundamentally new immunological approach to malignant tumors’ treatment and a practical method for its application in animals and humans at the advanced stage of the disease development.
Further elaboration of this line promises to result in the opportunities to exert a therapeutic effect upon the tumor process. Therefore, we appeal to you with an offer to show your practical interest in this development and to conduct check experiments in your laboratories to make sure that everything described in the book is a reality.
The proposed mode of an impact on the malignant tumor process can be regarded as an acting model of the method for malignant tumors’ treatment. To convert this model into the method to be recommended for clinical application, it is necessary to do a big work demanding significant scientific efforts and time.
Wishing to contribute to this work we are prepared for collaboration with the institutions concerned by providing all the information available on the details of the research and developments performed.
Yours sincerely,
Oleksandr Shevchenko Volodymyr Shevchenko Viktor Shevchenko
EPILOGUE
The concept to the role of immunity in pathogenesis of malignant tumor process and perspectives to affect it, stated in the book is based upon the results obtained in six blocks of science research, each of which has a fundamental character. We believe all the six blocks to be equal in its scientific significance and excluding at least one of them out of the concept structure will destroy it. Short about these blocks.
The first block is represented by works, performed by various authors in different time beginning from the late 19th century. They showed the presence of embryonic characteristics in all types of malignant tumors. Many researchers consider them the principal ones. Thus, for instance, a very authoritative scientist from Latvia, Ya.G Ehrenpreis, asserts in his monograph " Modern concepts of tumor growth" , that the base for tumor growth is embryonic properties of corresponding cells; no other specific properties, except for fetal ones, the tumor cells have.
The second block is represented by works, related to the phenomenon of malignant transformations of ectopic grafts of embryonic cells from embryos at pre-implantation period of their development as well as by research that demonstrated the phenomenon of malignant tumors noninoculability to embryos at the early stage of their development (Savinskaya, Whisson et al.) and finally by works of B. Mintz with her allophenic chimeras.
The third block is represented, in the main, by R.Prehn and his colleagues' research having showed the phenomenon of direct immunopotentiation of malignant neoplasms' growth by reactants of an organism's immune system and dependence of this immunostimulation upon
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the power of immunological action. It also includes theoretical generalization of the results obtained.
The fourth block is represented by works of J. Coggin and his colleagues. Their numerous and comprehensive investigations showed that all the tumors, either in humans or in rodents, as well as embryos at the early stage of their development contain universal embryonic antigens, being immunogenic in autosystems.
The fifth block is represented by our research results, described in the book. Their theoretical reasoning became possible only with involvement of the data, obtained in the other four blocks of research mentioned above.
Finally, the sixth block is represented by the developments of G. Chaouat end his collegues. If the investigations in all the previous five blocks were carried out within the framework of studies of the problem of malignant tumor growth, G.Chaouat's explorations relate to some other biological area. However, it is just they, which occupy a special place in the concept. Their result, just like the final chord in a musical symphony, makes the concept integral and complete.
At the same time, it is necessary to emphasize that the pivot of the concept is the idea that an organism's immune reaction to tumor antigens is the most important link in a pathogenetic chain of malignant tumor process formation and that suppression of this reaction should lead to cessation of the abovementioned process. This is a fundamentally new idea (was published in 2004 year) and, according to the preliminary investigation, considered as a fruitful and promising one.
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Please, contact us
Dr. Oleksandr V. Shevchenko V.Komisarenko Institute of Endocrinology and Metabolism, Acad. Med. Sci., Ukraine, Vyshgorodska Str., 69, 04114 Kyiv, Ukraine. E-mail: [email protected]
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Shevchenko O.V., Shevchenko Vol. O., Shevchenko V.O. The problem of malignant tumor growth. A fundamentally new solution. (Translated from Ukrainian). –– 22000099.. –– 7722 рр..
Translation B.Men
Computer make-up
S.Kalchuk
Pass a proof for press 14.12.2009 Format 84x108/32. Art paper.
Edition 500 copy.