The problem of malignant tumor growth

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The problem of malignant tumor growth. A fundamentally new solution

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The problem of malignant tumor growth

  1. 1. Oleksandr ShevchenkoVolodymyr ShevchenkoViktor Shevchenko The pr obl emof malignant tumor growth A f un dam e ntal l y new sol ut i on Kyiv 2009
  2. 2. УДК 616 ББК 55.6 Ш 38Shevchenko O.V., Shevchenko Vol. O., Shevchenko V.O. Theproblem of malignant tumor growth. A fundamentally newsolution. (Translated from Ukrainian). – 2009. – 72 р. In 1970-ies in the former Soviet Union in Kyiv (Ukraine) anefficacious immunological method for malignant tumors’ treatmentwas created. The complete recovery from transplanted and spontaneousmalignant tumors (even at the IVth stage of the disease) wasattained in a significant percent of cases in animals. Attempts to treat patients with tumors by means of this methodyielded hopeful results. The number of unique biological phenomena that had neverbeen described in science before were observed in individualscured 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 researchconducted, describe the results obtained and provide them withscientific explanation. © Shevchenko O.V., Shevchenko Vol. O., Shevchenko V.O. 2009 Gnosis, 2009ISBN 5-311-01319-2 2
  3. 3. Dedicatedto the blessed memoryof our relations: Zhana Shevchenko,Sita Bezpalko and Svitlana Bezpalko,who suffered from malignant tumors 3
  4. 4. 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 sponsors 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 organizingassistance during all the period of theoretical and practicalresearches as well as in preparing the book. 4
  5. 5. CONTENTSINTRODUCTION 6REVERSION OF MALIGNANT TUMORPROCESS: THE RESULTS OF 8STUDIES AND OBSERVATIONSCARRIED OUT The results of malignant tumors’ treatment 8 in animals The results of clinical observations 28METHOD OF MAKING AND 36APPLICATION OF ANTITUMOR DRUG“NEOREVERSIN”THEORY: A FUNDAMENTALLY NEWVISION OF AN ORGANISM′S IMMUNE 38REACTION IN PATHOGENESIS OFMALIGNANT TUMORS Specific immune reaction of organism as 38 initiator and promoter of carcinogenesis Discussion 59GENERAL CONCLUSIONS 67THE PROSPECTS OF 68IMPLEMENTATIONAPPEAL 70 5
  6. 6. INTRODUCTION In the early seventies of the last century ZoyaP.Uspenska, a kyivite phthisiologist, created animmunological method for malignant tumors’ treatment,based on placental extract, by means of which a significantpercent of cases of implanted and spontaneous malignanttumors in animals at their generalization stage as well as inoncology patients with neoplastic process at stage IV weresuccessfully completely cured. The immunological antitumor drug applied acquired itsconventional title as Reversin. In the middle of 1977 Z.Uspenska’s co-operation with theauthors of the present work began that had been going on indifferent forms for 9 years (until Z.Uspenska’s death). The results obtained aroused a wide interest in the circleof physicians, biologists and some administrative authorities(KGB of the former USSR, in particular). Several competent commissions were set up to check thefindings of Z.Uspenska and her co-workers with theparticipation of distinguished scientists: biologists,immunologists and oncologists. Among them were theworld-known scientists (Academicians A.P.Avtsyn,O.V.Baroyan and V.P.Komisarenko). They familiarizedthemselves with the results of the work performed and gavethem a high scientific appreciation, having pointed out to thegood perspectives and the necessity to proceed with furtherresearch in this direction. Despite an active support of the above, there have neverbeen any financial or organizing measures taken that wouldbe necessary to expand the research in this sphere. In 1984Z.Uspenska’s Laboratory was disbanded and the creativeteam 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. 6
  7. 7. 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 bythe authors as we were the most closely associated with herwork, by conducting the experiments on animals,participating in people’s treatment, etc. The researches were aimed at restoring the drug’sproduction technology as well as elaborating the theory of itstherapeutic effect. As a result, the work of the informal scientific team,consisting of Oleksandr Shevchenko, VolodymyrShevchenko and Viktor Shevchenko, has beenaccomplished at the creation of an antitumor immunologicalmedicine, called “Neoreversin” which, according to thepreliminary experimental study results, has the propertiesclose to the Reversin drug used before by Z.Uspenska. A new vision of the role played by an organism’s immunesystem in shaping the malignant tumor process wasscientifically substantiated, in light of which an explanation ofmost of the phenomena that had been observed in theconducted research was made possible, and primarily, thephenomenon of the reversion of malignant tumor process. 7
  8. 8. 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 rabbitsMethods Experimental study of the Reversin’s antitumor propertieswas begun on rabbits with implanted Brown–Pearcecarcinoma. Rabbits were administered a single subcutaneousReversin injection at the time when the signs ofgeneralization of the tumor process became apparently cleari.e.: the loss of appetite and flesh, tumor metastatic nodesbeing palpable in abdomen and under the skin or visualizedin eyes. Experiments on rabbits were conducted as from1971 through 1980 in various research institutions. Theexperiments’ results are summarized in the table shownbelow (Table 1). The efficacy of treatment was estimated by the followingcriteria: • 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. 8
  9. 9. Summary table of the results obtained in Reversin-treated rabbits with implanted Brown–Pearce carcinoma. Number of animals in a test Number of group animals in a Date of experiments conduction (The animals were treated) control group (The animals not Place of the treated) conducting Died experiments At the start of the At the start of the experiment Died from tumor treatment Survived Survived Died for other Died reasons Institute for Oncology 1971Problems of the and 51 37 11 3 25 __ 25 Academy of 1973. Sciences of the UkrSSR (Kyiv) Institute ofMicrobiology and 1971, Virology of the 1972, 70 57 13 ___ 52 __ 52 Academy of 1973.Sciences of theUkrSSR (Kyiv) Institute ofMolecular Biology 1976, and Genetics of 1977, 98 71 16 11 44 2 42the Academy of 1978, Sciences of the 1979, UkrSSR (Kyiv) 1980. Institute ofMicrobiology andEpidemiology of 1977. 5 3 2 ___ 5 __ 5the Academy ofMedical Sciences of the USSR (Moscow) Total 244 168 42 14 126 2 124 9
  10. 10. It is seen from the Table, that 168 out of 224 treatedrabbits have recovered, that consist of 75%. Out of 56 treated rabbits, witch were died in test groupthe 14 animals differ from other. They died in between the3rd and 4th months following the beginning of the treatment.The purulent broncho- or pleuropneumonia were found attheir autopsy and no signs of tumor process. If the 14 about mentioned rabbits were included into thenumber of animals cured from tumors then the percentage ofrecovery would increase to 81,3%. 10
  11. 11. The photographs of kidneys and liver of theReversin-treated rabbit slaughtered at anintermediate stage of recovery from the malignanttumor.Fig 1. The kidneys affected by metastases of Brown-Pearce carcinoma The photograph shows small dark hollows in the center ofmost of metastatic nodes. As it was proved by microscopicexaminations these were the zones of hemopoiesis. 11
  12. 12. Fig. 2. A section of the rabbit’s liver In the center of metastatic nodes there are the very samedark zones. Attracting attention is the fact that in the centerof the metastatic node, marked with a cross, there are onlythree tumor fragments left and in between the liver tissuestructure can be clearly visible. Assumption: the metastasescells were differentiated into the normal liver cells. 12
  13. 13. The results of the experiments conducted on rabbitsproved that after a single Reversin injection theregression of tumor and its metastases occurred in theorganism, and anatomic integration as well as thefunctions of the affected organs were completelyrestored. Pathologoanatomic examinations, including histologicaltests conducted on rabbits by V.N. Rachinsky, a fellow-worker of the Laboratory, give grounds to suggest that theBrown – Pearce carcinoma tissues were transformedafter the treatment into normal tissues of the organwherein the primary and metastatic tumor nodes hadbeen present. As it was shown in further research the blood serumof the rabbits cured of Brown-Pearce carcinoma, sometime later (from 7 to 8 months) following theadministration of Reversin, had acquired therapeuticantitumor properties that were manifested both inallogenic and xenogenic systems. This effect was extremely visibly displayed in theexperiment conducted by Oleksandr V. Shevchenko,Volodymyr O. Shevchenko and Mykola D. Tronko at KyivScientific Research Institute of Endocrinology andMetabolism. On December 12, 1977 two Reversin-treated femalerabbits, being in the stage of recovery from Brown-Pearcecarcinoma, were selected for the experiment. By thebeginning of the experiment all the signs of the tumorprocess had disappeared in both animals except for theresidual tumor metastases in the eyes as a greyish–whiteformation occupying a part of the eye’s iris. The blood of arabbit, suffering from carcinoma, was dropped into the eyesof both of the rabbits. On the third day after the blooddropping all the signs of malignant process stimulationemerged: the eyeballs began to increase and protrude out ofthe eye sockets. On December 20, the antitumor serum wasstarted to be dropped into the eyes of one of the rabbits. Aweek later the tumor regress became already visible.Meanwhile the other rabbit’s progressive tumor continued togrow. On January 7, 1978, the rabbit’s left eyeball projected 13
  14. 14. out of the eye socket by 2.5 cm and the right one – by 1,5cm. The eye lashes were unable to cover the eyes. That very day the other rabbit also started to undergotreatment in the same fashion (by the serum dropping into itseyes). Next day the dilated blood vessels were clearlyobserved in both of its eyes, and some days later a vascularplexus appeared in the shape of a ring around the necrosiszone, formed at the apex of the enlarged left eyeball. Antiblastic serum was dropped into the rabbits’ eyes for amonth’s time – first daily, then every second day and everythird day. A gradual resorption of tumors occurred in bothrabbits. And by the end of the 4th month since the beginningof the treatment the tumors’ complete regression wasachieved. The eyeballs acquired their normal size andshape. Both eyes of the first rabbit and the right eye of theother one resumed their eyes’ normal look with an openpupil. However, on the left eye of the other rabbit whereinthere was a large necrosis area, leukoma emerged. Dynamics of the tumor regression was especially vivid tooccur on the left eye of the second rabbit. This dynamics ispresented in a series of figures shown below. 14
  15. 15. Fig 3. The 2nd day after the beginning of the serumdropping Both eyes of the rabbit are dramatically projecting out oftheir eye sockets. The left one juts out by 2,5 cm. It shows atumor necrosis zone and the dilated blood vessel, whichhasn’t been observed prior to the beginning of the treatment. 15
  16. 16. Fig 4. The 6th treatment day. The view of the left eyeball The blood vessels that became more strongly dilated canbe clearly observed. Necrosis area is also seen occupyingthe entire eyeball zone. A demarcation line between thetumor and the necrosis zone starts to be formed. 16
  17. 17. Fig 5. The 32nd day since the beginning of the treatment The left eyeball has been significantly reduced in sizeand acquired a cone-shaped form. On the cone top thereappeared a crust. An intensive vascularization of scleraouter surface and reduction of the necrosis zone can beclearly observed. 17
  18. 18. Fig 6. The 52nd day since the beginning of the treatment The eyeball continues to diminish. There is an intensivevascularization of sclera. The necrosis zone has beenreduced, the crust has disappeared. 18
  19. 19. Fig 7. The 66th day since the beginning of the treatment.Side view The necrosis zone has disappeared. The tumor hasacquired a compact shape and the closure of eye lasheswas made possible. Hypervascularization of the eye is stillpreserved. 19
  20. 20. Fig 8. The 120th day after the beginning of the treatment The tumor in the eye has completely disappeared. Theeyeball has its initial size and form restored, however on thecornea where there was a necrosis zone, leukoma wasformed. 20
  21. 21. On the 120th day since the date of the treatment start noindurations were identified in the rabbit’s abdomen atpalpation. The rabbit was in the normal physiologiccondition. A year later after the experiment had been conducted theabove described rabbit was transferred to Moscow forfurther investigations. As it was founded out by the authors, no signs of theundergone neoplastic process were detected at theautopsy and histological analysis of the internals. When exploring the eyeballs the presence of all theanatomic constituents, characteristic of the normal eye,was stated. Out of pathologic abnormalities there waskeratoleukoma. An impressive result of the experiment was also that theregression of the tumor occurred in the setting of a sharpincrease in its vascularization. New biological phenomena found out in experimentson 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. 21
  22. 22. The results of treating horsesExperiment description The Reversin drug was also applied to treat 3 horses(two stallions and a mare), suffering from malignantneoplasms – melanosarcoma and melanoblastomatosis. (Asis known from the literature, melanotic tumors can be oftenfound in horses of grey breed.) A stallion “Vodiy”, born in 1961, of the Orlov trotter breed,was examined on 20.05.1973 by the VeterinaryCommission, headed by Professor I.O. Povazhenko, beingin charge of the Chair of Surgery at Ukrainian AgriculturalAcademy. A focus of melanosarcoma was detected in thehorse in the left prescapular region being two fists size, amelanosarcoma focus on the penis a hen egg size, and afocus of melanosarcoma near the anus being a wall-nut size.On the basis of the disease symptoms found theCommission arrived at the conclusion that it was inexpedientto treat the stallion and it was to be rejected as defective. At that time a stallion “Amper”, born in 1961, of the Orlovtrotter breed was also rejected as defective because ofmelanosarcoma disease. A great amount ofmelanoblastomatosis nodes were identified near the anus, apigeon-egg to a wall-nut size, as well as in the region of thespur vein on the left and in the area of the penis a plum size. On 14.09.1973 both stallions underwent the treatmentwith Reversin. On 4.05.1977 Reversin was also administered to treat amare “Pokrova”, born in 1958, of the Orlov trotter breed,which was rejected as defective because ofmelanoblastomatosis disease in the areas of the anus andudder in accordance with the Statement of 14.04.1977.Treatment results On March 24, 1979 all the three horses were examinedby the same Commission that had rejected them asdefective. The Commission came to the followingconclusion: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 22
  23. 23. 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, forthe mare was 2 years. The Commission made a conclusionof the efficacy of the method applied for the treatment ofmalignant neoplasms in horses. It is seen from the above mentioned that completereversion of the neoplastic process from its generalizationstage can be achieved in horses as well by means ofReversin.Biological phenomena, observed in treating horses Just like in the case with rabbits some concomitantphenomena were also observed with horses cured. The horses got rejuvenated which was displayed in theirrenewed capacity for work (they started to be used again foragricultural works to the full) and in their resumed sexualactivity, gone out already by the beginning of the treatmentas well as in their restored pelage colouring typical to youngspecimens: dapple - gray, three months after the treatment.This pattern disappears in old horses. They becomeuniformly light-gray. This phenomenon, i.e. the organism’s rejuvenescence inhorses cured from malignant tumors, can be the basis forthe assumption to be made that their lifespan could surpasstheir average indexes. Speaking in favour of this assumptionis the fact that the above described horses when deliveredfor slaughter (as they reached an average age for the Orlovtrotter equal to 22 years old) were still strong and capable ofworking with sexual activity preserved. 23
  24. 24. The results of treating mice In the experiments carried out on mice, Erlich carcinoma,a classic version of the malignant tumor disease served as amodel. A solid tumor process was induced by subcutaneousinoculation in the animals’ back or femur zones of a cancercells suspension in the form of a peritoneal exudate derivedfrom the abdominal cavity of mice, suffering from ascitic typeof carcinoma. Prior to the injection the exudate was dilutedby a sterile physiologic salt solution with 1:1 ratio. Theexperiments were conducted on white, non-thoroughbredanimals, as well as on the mice of CBA line. The animals’treatment started when a tumor node no less than 1cm sizein diameter appeared in the place of the cancer cellsinoculation. The attempts to treat mice suffering from the solidcarcinoma by means of Reversin yielded no positive results.However, the treatment of mice with antitumor blood serumof the rabbits, cured by means of Reversin, was a success.The serum was administered parenterally to mice. Thetumor ceased to be palpable in the experimental animalsduring the interval between the 20th and 30th days since thebeginning of the treatment. Totally 185 mice were used in the experiments. Therecovery of animals occurred in 40 through 60%. Beingbased 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 expandedregenerative abilities. It was found out on mice exactly that the range ofregeneration processes in animals, cured of malignant 24
  25. 25. tumor, can be strongly expanded right up to the possibility oforganotypical regeneration. This phenomenon was not anticipated and it wasdiscovered quite occasionally. A group of mice cured oftumor that were regarded as being worked off, were kept forseveral months in a vivarium for the purpose of theirpossible use in other experiments. During this time period the mice’s tail ends, cut off tocollect blood during the experiment, were noticed to grow.The procedure of collecting blood from mice’s tails after theirends being amputated is a routine method widely used allover the world. However, nobody has ever observed the cutoff tail parts being regenerated. Thorough investigationsproved that this phenomenon was a result of the animals’recovery from the malignant tumor. A histological analysis ofthe regenerated tails’ parts was performed. A histologicalpreparation was made in Professor Sementsov’s Laboratoryat Burdenko Military Hospital (in Moscow). The Laboratorycomments weren’t preserved but those histologicalpreparations were also studied by K.M. Tantsyura, AssistantProfessor at Pathoanatomy Department of Kiev MedicalInstitute. The expert testified to the fact that “in the referredmaterial the bone regeneration occurred, which passedthrough the cartilage stage; the shaping of bone beams wasobserved with the presence of bone marrow cavities filledwith marrow”. The phenomenon of a tail’s end regeneration has alsobeen reproduced in Kyiv Scientific Research Institute ofEndocrinology and Metabolism. Its description is shownbelow.Description of the experiment on reproducing thephenomenon of an amputated tail’s part regeneration inmice cured of Erlich carcinoma by immunological methods. In March 1978 Z.P. Uspenska, head of the Laboratory forCell Protection Mechanisms at the Institute of MolecularBiology attached to the Academy of Science of the UkrSSR,proposed us, O.V.Shevchenko, head of the Laboratory forExperimental Pharmacotherapy at Kyiv Scientific ResearchInstitute of Endocrinology and Metabolism attached to theMinistry of Health of the UkrSSR, M.D.Tronko, academic 25
  26. 26. secretary of the same Institute, a senior research worker atthe Laboratory for Pathophysiology and G.F. Matvienko, aveterinary physician being in charge of the Vivarium at thesame institute, to conduct a check experiment onreproducibility of the phenomenon of an amputated tail’s partregeneration in mice, cured of a solid Erlich carcinoma type.To conduct the experiment an antitumor serum preparationwas obtained from the Laboratory for Cell ProtectionMechanisms by the Pharmacotherapy Laboratoryrepresented by O.V.Shevchenko. On 15.03.1978 four non-thoroughbred white female miceweighing 16 to 18gr. were subcutaneously inoculated in thefemur area with Erlich carcinoma in the form of 0.2 ml 50%ascitic fluid derived from the mice suffering from an ascitictype of this tumor. The treatment was started 12 days laterwhen tumors of 1x1.5 cm size developed in the mice in theplace of inoculation. Antitumor drug was administeredsubcutaneously of 1.0 ml every second day right up to thetotal tumor regression (as determined by palpation). Thetumors in the experimental animals ceased to be determinedby palpation during the interval between the 20th and 30thdays since the beginning of the treatment. At the moment,when the tumor tended clearly to diminish, the tails’ parts 1.5to 2cm long were amputated in those four animals by meansof a sharp scalpel. Hemostasis was made by means of aconcentrated Kalii permanganas solution. Over a month’s time the wounds got healed by thesecondary intention and covered with epithelium. During thenext two months of follow-up an outward appearance of thetails’ stump wasn’t notably changed. The experiment wasconsidered to have failed – a tail regeneration phenomenonwas not reproduced. Therefore three of four experimentalmice were used for other experiments but one mouse stillremained. Soon owing to the force of some circumstancesits distal vertebra stripped itself in the place of amputation.Some time later next to the mummified vertebra thereappeared a projection that began to extend. By the end ofNovember, i.e. 8 months later after the amputation, theprojection took shape of a tail’s regenerate though a bitdeformed but with all the signs pertaining to the organ:epithelial scales, mobility and hair. 26
  27. 27. Thus, a phenomenon of the amputated tail’s partregeneration was fixed by us on one adult mouse, cured ofErlich carcinoma. The picture with the tail‘s regenerate isshown below.Fig 9. Regeneration of the tail’s end in a mouse cured ofErlich carcinoma by the immunological method This experiment’s result has one more peculiarity. As isseen from the picture the growth of the regenerate occurrednot out of the amputation surface but sideways whichresembled the sprouting of a plant branch out of a side bud. The cured mouse with the irregular tail’s endregeneration was transferred to Moscow for furtherinvestigation. The results of the experiments carried out at KyivScientific Research Institute of Endocrinology andMetabolism were reported to the President of the UkrSSRAcademy of Science by the Director of the Institute -Academician V.P. Komisarenko.2. The phenomenon of lifespan extension in the curedanimals Alongside with the phenomenon of expanding anorganism’s regenerative capability in the mice cured of theimplanted Erlich carcinoma, a tendency to extend theirlifespan was also established (in the average of up to 2.5years against 1.5 years in a control group). The implantation of tumor was performed according tothe generally accepted methods. 27
  28. 28. THE RESULTS OF CLINICAL OBSERVATIONS After the Reversin and antitumor serum atoxicity wasproved by injecting a 10-fold therapeutic dose into intactanimals as well as one therapeutic dose into a healthyhuman (to Z.P. Uspenska) the antitumor treatment by theworked out method was applied to some of the patients ofclinical group IV, with a blastomic process at stage IV onrequest of the patients themselves or their relatives. The diagnosis of the disease used to be always verifiedin specialized oncology institutions. A positive result was established in both female and malepatients 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 schematicdescription of a generalized picture of clinical manifestationsin organisms of the patients suffering from malignant tumorsto 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’sorganism 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’ssubcutaneous or intramuscular injection are of a vascularnature. Several minutes later hyperemia emerges around theplace of injection. Following it the blushing of cheeks, nose,ears, palms and all the visible mucosa as well as that of thenail beds and postoperative scars was generally observed. Te patient at this time can have caumesthesia on the skinof the face. 28
  29. 29. Sometimes there occurred reduction or change in thecharacter of pain sensations if they had been present prior tothe treatment start. Following hyperemia around the point of the skinpuncture there emerges a papule of 3 to 15 mm in diameter.It normally disappears 10 to 15 min later while hyperemiamay last for some hours more, though directly in the point ofa puncture it may last up to several days. The period of secondary reactions This period is conditioned by the processes proceeding inthe area of tumor nodes’ localization as well as by thegeneral reactions. It is distinguished by a significantpolymorphism of symptoms, the presence andexpressiveness of which depend on the tumor size, itslocation and metastases as well as on patient’s state at themoment of the treatment start and the presence ofconcomitant diseases. The following symptoms can be observed during thisperiod. In the setting of normal or somewhat increased bodytemperature in patients there appears a feeling of “hot flush”or fever (sometimes very high) being localized in the tumoreffected areas. These phenomena are associated with xerostomia andthirst. Sometimes there appears a subjective feeling of ahigher temperature in the entire body. Physically thetemperature doesn’t exceed 37,5°C. Specific for the second period are also changes in thepain syndrome. The nature of pain sensations is generally changed afteradministering the Reversin drug. Sometimes the decrease inpain or even its complete disappearance occurs. On thecontrary the pain can sometimes rise which may beassociated with edema occurring periodically and resulting incompression of organs or nerve trunks. Typical of thesepains is their periodical nature. During this period mucosa and skin hypersensitivity todifferent mechanical, chemical and thermal stimuli can beobserved. 29
  30. 30. During the recovery period a “creeping” sensationappears periodically in the region of tumor nodes. If the tumor process was widely spread one couldobserve a temporary impairment of the patients’ generalstate in the second period which was likely to be associatedwith the resolution of necrosis masses that were alwayspresent in large tumor nodes. In this, general weakness, nausea, vomiting, a feeling ofrheumatic pain all over the body and constipationsalternating with diarrhea can be observed. In the setting of polymorphism of the symptoms specificto the second period of reaction some cyclic recurrence oftheir manifestations can be traced. First (during the first days) they were observed to occursome cycles a day. Then they appeared rarer. The cyclic reaction may be observed to occursimultaneously in all the tumor effected areas, though it canfirst cover some zones only, moving on to the others in adue course. The second version of the reaction course ismore favourable. With the favourable progress of the process the abovementioned symptoms’ manifestations go gradually out andthen disappear completely. The reaction passes on to the3rd period - that of the complete recuperation lasting forabout a year, typical of which is the absence of any specialsymptoms not to mention the enormous increase in appetitethat turns sometimes into a “gargantuan” appetite (thepatient eats up much food, he even dreams about it at night,especially about the forbidden foods). Despite the qualityrestricted diet the body weight sometimes augments veryquickly and can exceed by far the initial weight coming tonorm during the following years only. During a year’s period there occurs completedisappearance of the tumor and its metastases as wellas substitution of the tumor-induced defects and also ofall the tissues with the corresponding full value tissuesin morphological and functional respect (in the liver - bythe hepatic tissue, in the lungs – by the pulmonarytissue, in the skin – by the cutaneous tissue, etc.). 30
  31. 31. Changes in an organism’s responsiveness duringthe treatment process According to the literature data as well as to ourobservations the responsiveness of patients with expandedtumor lesion is dramatically deteriorated which is shown inthe inhibited inflammatory reaction, in particular. Variousdermal abscesses disappear, in particular. A favourable sign testifying to an increase of theresponsiveness in a tumor-host (observed normally 2 to 5weeks later after the beginning of the treatment in most ofthe patients) was the eruption of abscesses on the entirebody (as from a single one to dozens of them). Theabscesses soon disappeared. The patients during this period became hypersensitive toinfectious diseases of cold type, in particular. Theprogression of infection may lead to the reaction“breakdown” which will be commented on later. Further on with the favourable reaction progress theorganism’s responsiveness gets gradually normalized. In addition, during the patients’ treatment a problem ofsymptomatic therapy arises. In the course of antitumortreatment the organism’s sensitivity to the whole range ofmedicines (cardiac glycosides, nitrates etc.) turned out togrow dramatically. The above preparations as administeredeven in the usual therapeutic doses could cause very severecomplications. 31
  32. 32. Biological phenomena observed in clinic1. 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. 32
  33. 33. The reaction – associated complications The above described reaction appeared in almost all ofthe patients in response to the drugs injection. It was morepronounced after the Reversin injection. In case of theserum injection its manifestations were considerably less. However, not all the attempts to treat people weresuccessful. 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 thereaction may proceed rapidly and violently. In patients thereappeared a state resembling the picture of kinin shock:mental blankness, hemorrhage out of all the mucousa anddeath. This complication was observed rarely, it was stated onlyin two incidents and only after the Reversin injection.2. “Breakdown“ of the reaction The most frequent reason for the treatment inefficacywas a complication, entitled as the reaction “breakdown”. By this term we define a disease course during whichpositive tendencies in the development of the recoveryprocess terminated allowing the negative ones to occur, thatare characteristic of the resumption in the disease process. After the reaction “breakdown” the tumor growth assumesa progressive character which leads to a patient’s death. Clinically the “breakdown” of the reaction is determinedby disappearance of the symptoms typical of the favourableflow of the reaction and by recurrence of a set of symptomscharacteristic of the progressing tumor disease. The “breakdown” often happened when the patient failedto keep to the diet; it occurred as well without any visiblereasons when there was a flaccid (hypoergic) reactionprocess. An early laboratory sign of the unfavourable reactionprocess is a decrease (sometimes dramatic) in thepercentage of lymphocytes’ content in peripheral blood. 33
  34. 34. After the reaction “breakdown” the character ofrelationship between the host and the tumor returns to thestate similar to one that existed prior to the beginning of thetreatment. The similar state is but not the identical one.Testifying to this is the fact that attempts to resume thereaction by the repeated Reversin drug or serum injectionfailed.Prevention of the reaction-related complicationsPrevention of the reaction generalization In so far as generalization of the reaction was establishedin the cases of Reversin application only and it was notobserved in any other case with serum treatment it isadvisable 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 fora year following the antitumor drug injection their foodshould not contain any components of the animal origin. The inclusion of these kinds of products even inmicrodoses into the rabbits’ ration during the treatmentprocess led to their death as a result of stimulation ofblastomatous process. In the course of further research a special diet has beenworked out. The strict keeping to the diet is compulsory inthe treatment of all the experimental animals as well ashumans. In our opinion it was the very factor of failure to keep tothe diet that accounted for the reaction “breakdown” in thepatients’ treatment. The difficulty in keeping to the diet wasthat all the patients in all the above cases stayed at home infamily surroundings the members of which mostly didn’t altertheir traditional way of having meals. 34
  35. 35. Indications and contra-indications for applying thenew treatment methodIndications Indications to apply the method were worded with regardto the conditions wherein the laboratory employees couldhave an opportunity to perform the treatment. Medical indications: the presence of the diagnosis of malignant tumor processof 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 workedout treatment method is a previous chemotherapy. Of all the above stated, one can make a conclusionthat the clinical observations carried out, despite thepatients’ incomplete clinical examination during thetreatment, strongly testify to the antitumoral therapeuticefficacy of both Reversin and antitumor serum. 35
  36. 36. 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 isnecessary to have two components: extract of placenta andblood of cancer bearing hosts. Method of making an extract of human placenta The procedure of making a placental extract is carried outwith the greatest observance of aseptic rules. Human placenta is obtained from natural physiological orartificial cesarean deliveries (the latter is better).The placenta is minced in slices approximately of 2 – 3 sm3in size (the size of parts has no importance). The placenta is placed in a sterile vessel. Then there thesterile physiological solution is added in amount 0,5-1,0parts in relation to placenta weight. The vessel with placenta is placed in a refrigerator at+20С – +40С for 3–4 days. 36
  37. 37. Media (placental extract) is harvested and kept at +20С – 0+4 С 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 biologicalcomplex which is produced directly before its use (extempore). 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 bearingrabbit (0,7 – 0,4 ml) is added. The components are mixed bythe 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 thecomponents is transformations of the mixture in a syringeinto gel in an interval of time from 10 to 20 minutes ofexposition. Mode of application of “Neoreversin” The “Neoreversin” is injectied into the rabbit body byhypodermic or intramuscular injection in amount of 2 – 2,5ml per one animal. After the treatment the rabbits should be at complete rest. The diet – exclusively plant food. 37
  38. 38. THEORY: A FUNDAMENTALLY NEW VISION OF ORGANISMS 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 CARCINOGENESIS 1 (hypothesis) Having considered the published data, but devoid ofrational explanation in due time, the authors put forward ahypothesis about the decisive role of an organism’s specificimmune reaction in pathogenesis of malignant tumorprocess. The hypothesis was shown not to contradict acontemporary vision of the mechanism of malignant tumordevelopment. It was concluded that the induction in tumor-hosts of immune tolerance to tumor antigens makesretransformation 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.Gibbs1 “Journal of Medical Science Academy of Ukraine”, 2004, v.10,№1. – p.50-64 UDC 616-006.04:612.017.1 (Recommended byCorresponding Member of MSA, Ukraine V.A.Mikhnyov) 38
  39. 39. The problem of immunologic interrelations betweenmalignant tumors and host is very complicated and intricate.More than a hundred years have passed since theexperiment showed the possibility for cancer immuneprevention, but the creation of highly efficaciousimmunologic modes to treat malignant tumors is still waitingfor its time to come. When starting to present our vision on one of theimmunological approaches to solving the problem ofmalignant tumor growth we find it necessary to submit aconcise description of its general picture while dwelling atsome greater length on those chapters only which aredirectly associated with the idea asserted in this publication. As back as the early 20th century S. Jensen publishedhis work wherein he, being based upon the results obtainedin the performed research, stated the idea concerning thepossibility to artificially create an active immunity tomalignant tumors [29]. Soon after, P.Erlich with hiscolleagues joined in studying this problem [40]. In thefashion analogous to the methods, applied in bacteriology,they immunized animals with avirulent tumor material,developing their resistance to inoculation of already virulenttumors. However, the interest to the research in this areadecreased and up to the middle of the last century onlyisolated reports appeared about the works dedicated tostudies of the immunity to tumors. It’s not until the works byE.Foley [28], R.Prehn and J.Main [37], R.Beldwin [21] andothers had been published that the researches in the field oftumor immunology were dramatically activated. Using auto-and syngeneic systems, researchers clearly identified thepresence of the phenomenon of antitumor immunity. Theanimals, previously injected with inactivated malignant tumorcells, gained resistance to inoculations with the living tumormaterial. Almost all the elements (humoral as well as cellularones) of the immune system were found, and not only inexperiments but also in clinic, to be involved in the formationof antitumor immune reaction. However this mechanismdoesn’t ensure any protection against malignant tumorgrowth in natural conditions. This is associated with anumber of circumstances. As it has become clear, along withthe evolvement of immune reactions having an antitumor 39
  40. 40. trend, their blocking mechanisms come into action. Apartfrom this, there’s one more phenomenon making thesituation much more complicated – it is immunostimulationof tumor growth (this phenomenon will be regarded in detailfurther on). Such interweaving of the processes, havingdifferent trends, is apparently responsible for the currentstate of the immunotherapy, when it is capable ofperforming, and not always though, a secondary role only.To make sure that it is really so, one can open the lastedition of the capital manual on the treatment of malignanttumors “Cancer Medicine” [20]. The following is said thereabout the possibilities of the immunotherapy: “…favorableresults of the immunotherapy can be observed only inpatients having microscopic manifestations of the diseaseprovided that the adjuvants were applied after all the clinicaltumor manifestations had been eradicated by means oftraditional treatment methods”. Nowadays titanic efforts are being made to boost anorganism’s immune reaction to the efficient level by meansof antitumor vaccines. A great number of researchinstitutions and firms are engaged in creating them. [19, 26,27, 31, 32, 41]. However, not all assess unambiguously theprospects of this direction. So, R. Prehn, a lead theorist inthe area of antitumor immunity problems, for example, treatsit with caution, admitting though the perspective of antitumorvaccination with embryonic tissues [34]. When analyzing pathogenesis of malignant tumors, wepaid attention to the phenomenon of malignanttransformation of embryonic cells transplanted into ectopic(extrauterine) sites of adult syngeneic animals. Thisphenomenon has not received any unified theoreticalinterpretation as yet. Its exceptionality consists in the fact that embryonic graftsundergo malignant transformation without any carcinogenicimpacts, i.e. there takes place carcinogenesis withoutcarcinogens. This fact became the basis for shaping ourviews as to the role of an organisms immune reaction incarcinogenesis which differed from those generallyaccepted. In the late 70-ies and early 80-ies of the 19th centuryJ.Cohnheim’s views concerning the origin of malignant 40
  41. 41. neoplasms were shaped [25]. According to J.Cohnheimmalignant tumors can be developed either from theremaining embryonic tissues that happened to be among thedefinitive tissues of the same histogenesis but, due to somereasons, were not involved in the normal tissue buildingprocess, or from the embryonic residues, transferred toanother site, which appear to become a heterotopic objectand therefore are not involved into intratissular interrelations.These embryonic residues give rise to neoplastic growth. Inorder to prove or disprove this hypothesis the embryonicmaterial (tissues or embryos’ parts) was transplanted intoadult animals however there was no growth of tumors fromthem. But when embryonic cells, isolated from the embryosin pre-implantation period, were implanted into theextrauterine sites of adult syngeneic animals, they werenaturally transformed into malignant ones. A well-knownexpert on the problem of malignant cells’ differentiation,I.Shvemberger spoke on the subject as follows: “The factthat no tumors develop in the case of the ectopictransplantation of definitive tissues allows the ectopic grafts’malignant transformation from embryonic tissues to beassessed as a particular case of carcinogenesis, that byetiology, pathogenesis and prognosis should be consideredindividually” [15]. However, the author of the work doesn’t gobeyond these recommendations. In the literature of the following years we haven’t foundany attempts to provide this phenomenon with anytheoretical interpretation either. Although in our opinion itsuggests the existence of some intrinsic cause fortransformation of embryonic cells into malignant ones. It isunclear whether this cause can have any relationship toother cases of carcinogenesis. It can’t be excluded thatdetermination of the nature of this intrinsic factor andinduction of neoplastic transformation will enable one to findanswers to some other questions as to the mechanism ofmalignant tumors origin. About 30 years ago G. Svet-Moldavsky [9] explained thisphenomenon as follows: in embryos there exist somepowerful cellular and humoral factors regulating theembryonic cells capacity to grow and differentiate. They areabsent in an adult organism. If embryonic cells are 41
  42. 42. reproduced in the organism where there are no factorsregulating their growth and differentiation, they’ll becomemalignant. In a theoretical study “Embryonic Properties of TumorCells: Facts and Hypotheses” Ya. Ehrenpreis [18], touchingupon the problem of extrauterine embryonic grafts’neoplastic transformation, points out, that the reason for it isnon-embryonic conditions of such grafts cells’ existence buthe doesn’t specify what factor of these conditions exactly isdirectly responsible for neoplastic transformation. And on thebasis of his monograph “Contemporary concepts of tumorgrowth” [17] only, published in 1987, does it appear that he,like G. Svet-Moldavsky as well, sees the reason for suchtransformation in the absence of embryonic inductors ofdifferentiation in the adult organism. Such ideas are quitelogical. Actually in embryos normally not only does thegrowth and differentiation of embryo’s own cells occur but sodoes the differentiation of cancerous cells transplanted intothe embryo [30]. However the blank side in thesehypotheses is the fact that many attempts to isolate thedifferentiation factors out of embryos yielded no convincingresults. Embryonic extracts, being not infrequently far frominhibiting, have even stimulated neoplasias’ growth. But rightful can also be another assumption, viz.: in adultorganisms there’s a certain factor that induces malignanttransformations of embryonic cells which is absent inembryos. What kind of factor can it be? One of thedistinctions between embryo and an adult organism is thepresence in the latter of the immune-reacting system and itsabsence in embryos. So, perhaps, the very system itselfcontributes to the fact that cells, having embryonicproperties, become malignant while being transplanted intoan adult organism? We are aware of some paradoxicalcharacter of such an assumption since usually the effects ofan entirely opposite nature are associated with the immunesystem, as It is the one, which, in compliance with the theoryof immune surveillance, resists the development ofmalignant neoplasms. Nevertheless, it is well known thatimmune reactions in an organism are being far from playingalways a protective role. A lot of examples can be given toshow that they are an important and sometimes even a key 42
  43. 43. factor in the development of diverse pathologic processes,severe ones included [6]. Let us regard some other arguments speaking in favor ofour assumption. Let’s begin with the most principal one. Anumber of embryonic cellular markers include substances ofprotein nature with inherent antigenicity in an adult organismin auto- and syngeneic systems. Therefore the embryoniccells that happened to get into the adult organism will besubject to the action of various effectors of the immunesystem. And this impact will undoubtedly have certainconsequences for embryonic cells, that will be manifested ifnot in their destruction but then in some serious functionaldisorders, for instance, in differentiation disturbances. Thusthe immune reaction seems to be capable of acting as adestabilizer of the situation. We don’t see any othercandidates for this role to play. Let us word this hypothesis as the following postulate:the factor, transforming embryonic ectopic grafts intomalignant ones in adult animals in syngeneic system,represents an organism’s specific immune reaction. Let’sconsider further on, whether this postulate can be applicableto the cases of carcinogenesis occurring under naturalconditions and can be modeled in the experiment, viz.: toblastomas, induced by diverse carcinogenic impacts, as wellas to the tumors of viral origin and to spontaneous tumors. Let us refer again to Ya. Ehrenpreis’ views oncarcinogenesis[17]. According to his ideas normal embryoniccells are initially endowed with neoplastic potencies that arerealized in the form of malignant growth when embryoniccells happen to get into non-embryonic conditions of theirexistence; tumor cells are embryonic cells, devoid of theposibility to participate in normal embryogenesis. As forsomatic cells, giving rise to tumor growth, they gainembryonic properties and, consequently, also a potency toneoplasia during the latent period of carcinogenesis. Sinceembryonic properties, in this case, are transferred to cells,not designed for embryogenesis, their further existence ismanifested as tumor growth. If we consider somatic cells, embryonized under theimpact of carcinogenic factors, as the particular ectopicembryonic grafts, then the above worded postulate may be 43
  44. 44. applicable, in fact, to all of the versions of carcinogenesis.But in that case it seems to come into conflict with oncogenetheory, by which the only reason for cells neoplastictransformation is derepression of oncogenes in them and noother conditions for it are required. That is to say the eventof oncogenes’ derepression alone is already sufficient formalignant transformation to take place. To make these discrepancies agree, oncogenes’functions should be analyzed in detail. Most of the scientistsbelieve that oncogenes play a very important part in anorganism (common to all species of living organisms), that ofregulating the cells’ growth and their differentiation [4].Various oncogenes in placental animals are found to beexpressed freely in certain periods of their embryonicdevelopment and it is quite natural that at this time they areresponsible for an organism’s cellular and tissuecharacteristics, which we call embryonic ones. Oncogenes inthe process of an organism’s development are repressed.But if they start functioning in an adult organism, then theproducts of their activities appear to be immunologicallyheterologous for the mature organism and a typical immunereaction is developed in respect to them. Taking into account all the above-stated, the mechanismof malignant process origin is conceived by us as follows.Under the impact of some external or internal factors inorganism’s cells there occurs derepression ofoncogenes. The direct result of activities of the latter isoncoproteins and other biologically active compounds,embryonic antigens included. In respect to them theorganism develops an immune reaction that deformsthe vital activity of cells containing activated oncogenesto such an extent, that they lose their capacity fordifferentiation and get transformed into malignant ones. This vision of a sequence of events doesn’t deny theoncogene theory, but on the contrary would rathercorroborate it as it eliminates the logical difficulty thatbewildered 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 hiddena cancer mechanism for such a long time. What was 44
  45. 45. observed, was in one respect distressing since the chemicalmechanisms, that apparently “pushed cells off” onto thepathway of malignant growth, did not differ at all from themechanisms operating in normal cells” (cited by [10]). We will cite here one more statement. “The oncogeneconcept, for all its advantages as compared to otherconcepts of carcinogenesis, has at least one vulnerable link.Scientists tried to understand how the cellular genes beingnormal and apparently necessary for the vital activity, whenundergoing their minimum alteration (and sometimes,maybe, without any but only as a result of their increase inquantity), become detrimental for the cell and the organismas 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, isincapable to resist their harmful action?” [10]. In accordance with the postulate proposed, the problemof this contradiction can be solved in rather a simple way.Actually, the chemical mechanisms (meant here areoncogenes’ products and biochemical functions, broughtabout by them) operate in a similar way both in tumor cellsand in normal embryo cells. No matter whether oncogenesfunction in embryo cells or in an adult organism’s cells oreven in the cellular culture, the result will be identical. Thereare no reasons to think that their activities’ products canhave different properties insofar as oncogenes’ nucleotidematrix remains one and the same in all the cases shown.The whole point is that the organism’s reaction to thederepressed oncogenes’ products in the period ofembryogenesis and in the adult state is different. Therefore itis not the chemical mechanisms as such that trigger tumorprocess but the organism’s immune reaction “pushes” thecell, embryonized as a result of oncogenes’ disinhibition, offthe normal pathway of differentiation. In this connection it is necessary to consider a wellstudied phenomenon – the phenomenon ofimmunostimulation of tumor growth, playing an importantrole in pathogenesis of malignant tumors. However, today ithasn’t yet been given due attention either. This phenomenonwas identified when studying the immune reactions’ impactupon the tumor process. Its manifestations were unnaturaland unclear. The reason for immunostimulation was first 45
  46. 46. believed to be some factor, not yet explored, that was eventermed as XYZ to emphasize its enigmatic nature. Howeverit was revealed very soon that this factor’s nature doesn’tdiffer at all from the already known immune reactions. The facts about the tumors’ immunostimulation havebeen accumulated and finally an attempt has been made totheoretically construe them. The tumor growth was believedto be enhanced due to the blocking factors that impaired theantitumor action of immune reactants and the tumor cellsstarted to reveal more freely their potential to rapid andunlimited growth. But such a view was radically changed onthe boundary between 60ies-70ies, after R. Prehn startedworking on this subject. At first the results of hisexperimental works were published followed then by afundamental theoretical study carried out by him togetherwith M. Lappe [36]. This work showed that it was the directaction of immune system reagents that led to the stimulationof tumor growth. This kind of effect is induced by theimpaired immune reaction while the strong one isresponsible for the inhibition of tumor growth. Some timelater, a series of experimental and theoretical works by R.Prehn and other researchers appeared to add arguments infavor of the theory of tumor growth immunostimulation. The opposite trends of the weak and strong immunereactions’ action upon tumors isn’t something extraordinary.It represents a well-known regularity consisting in that thesmall doses of biologically active agents (even toxic ones)stimulate the functions of biological systems while the largeones – inhibit them. A great number of examples can begiven to confirm the universality of this principle. Thereforethe immune action on tumor cells isn’t an exception. Theaction of the weak immune reaction upon a tumor will be thatof stimulation but with its power being increased thestimulation terminates and the inhibition starts. The arrivalof this moment depends on the “stimulation width” (let’s thusterm it) of the immune action, i.e., on the range between thepower of immune reaction, when the stimulation just begins,and its level when the stimulation is over. In pharmacologycorresponding to this notion is “therapeutic range” of drugs’dosage. 46
  47. 47. Based upon observations of the tumor growth in diverseversions of the experiment, R. Prehn has worded a postulateby which every tumor in order to be stimulated requires theimmune reaction of such a magnitude and character, that ispeculiar to it alone [35]. Insofar as the specific immune reaction to the tumorarises 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 thisaugmentation. Integrated power of the immune reaction inreality doesn’t ever reach magnitudes at which tumordestruction starts. It remains always weak and acts as astimulator of tumor growth. In the early 80-ies of the 20th century A. Ageenko andco-authors performed a series of works, the results of whichare fundamentally important in terms of our knowledge of theimmune reaction role in pathogenesis of malignant tumorgrowth. The authors put forward their own concept of therole the immune system plays in pathogenesis of malignanttumor growth, the underlying idea of which implies theparticular importance of embryonic antigens in theprocesses of tumors’ origin and progression [1]. On thesurface of transformed cells at least two antigen groupswere shown to be expressed that mediate a differentqualitative result of immunologic interaction between tumorsand lymphocytes – immunocytolysis and immunostimulation.The latter significantly exceeds immunocytolysisis in itspower and is realized in the line of stage-specific embryonicantigens. The authors arrive at the opinion by which “it can’tbe excluded that immunostimulation is the mechanism thattriggers carcinogenesis and might afterwards play anessential role in tumors’ progression”[1]. Thus theseinvestigations proved that an organism’s immune reaction tothe transformed cells plays an important role. We consider it necessary to make here a short digressionin order to introduce an extraordinary essential specification.We use the definition of “embryonic antigens” in relation tothose substances only, that being typical of embryos at theearly stage of ontogenesis, start to be expressed onplasmatic membranes of transformed (i.e. embryonized) 47
  48. 48. cells and are immunogenic in autochthonous hosts andsyngeneic systems, and also activate T-lymphocytes. It isimportant to emphasize this as the term “embryonicantigens” is used widely enough in relation to a number ofsubstances that don’t generate any immune reaction inhosts nor do they activate T-lymphocytes. These are, forexample, α-fetoprotein and carcinoembryonic antigen thataren’t actually the specific markers of tumor process, but themarkers of proliferation alone. The importance of thiscircumstance was emphasized by J. Coggin [22], whoindicated two antigens, in particular, which were expressedin embryos and malignant tumors only and couldn’t beidentified in any other normal tissues by means of the mosthigh-sensitive technique. These are glycoproteins withmolecular masses of 44 and 220 kDa. The fact, that such embryonic antigens have beenidentified in all the tumors studied, without regard to thesource of their origin (ecto-, endo- or mesodermal) and aspecies-specific belonging of the hosts (human, rodents)[22-24,39] suggests the presence of universal features inmalignant tumors. If we take into account this circumstanceand an extraordinary limited quantity of these features, then,finding the method to appropriately affect them, would makeit possible to work out a unified approach to malignanttumors’ treatment. Returning to the main subject of our study, we may statethat an organism’s specific immune reaction in respectto malignant tumors is protective only in theory. Inreality, it is one of the initiating factors of neoplasticprocess and its promoter. Proceeding from the stated ideas on the mechanism ofneoplastic process formation and development, malignanttumors should be interpreted as autoimmune pathology.Richmond and Lisa Prehn in their article “AutoimmuneNature of Cancer” [38] wrote the following: “Since theimmune reaction facilitates oncogenesis by MCA, MCA-induced cancer can legitimately be termed an autoimmunedisease”. In this, the authors consider the MCA system isn’tlikely to be a unique one. Therefore they believe that when itbecomes known how to prevent autoimmune diseases, it willbe possible just as well to prevent not only the development 48
  49. 49. of MCA-induced cancer, but also the majority of malignanttumors. A. Ageenko and V. Yerkhov single out anautoimmune constituent of carcinogenesis too [1]. We, as distinguished from the many researchersmentioned, believe that the immune system not juststimulates the neoplastic growth, but we also substantiatethe statement, that it is a malignisative factor for cells,expressing embryonic antigens; that it is the immunesystem that plays a key role in the mechanism ofmalignant process formation and development. Thesignificance of diverse carcinogenic effects comes thus totheir capability to derepress oncogenes at that time, when ahighly powerful system of non acceptance for their productshas been already formed, namely, the immune system. Itprovides more grounds to speak of the malignant tumors asa variety of autoimmune diseases. Let’s now have a look at the other versions ofcarcinogenesis and the experimental schemes to fight thetumor growth in light of our postulate. Let’s dwell at first uponthe general theory of cancer by A. Cherezov [13] accordingto which the reason for malignant tumors origin lies in thetissue homeostasis’ disturbance. In correspondence to theauthor’s ideas the structure of tissue homeostasis consistsof the various tissues’ stem (cambial) cells having a highproliferation 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 ofnatural deterioration and destruction. The strictly measuredfunctioning of stem cells, which corresponds to the scopes ofnatural losses in the deteriorated differentiated cells, isensured by the mature cells’ capability to producesubstances, (chalones), having the property to inhibit thecambial cells’ proliferative impulse. Under the action ofvarious carcinogenic substances there occursdisarrangement of feedback mechanisms and the cells’proliferation process begins to prevail. Many young cells thathave no time to differentiate are accumulated in tissue andthere occurs the tissue embryonization. As a result, thetissue homeostasis structure and also then its function aredestroyed and a tumor originates. But it remains unclear 49
  50. 50. when the moment comes for the accumulated aggregate ofyoung embryonized cells to cease being the normal tissueand to be transformed into a malignant one. We don’t findany answer to this given by the author of the research. Ifviewed from the standpoint of the postulate underconsideration we will see the answer to it lying right on thesurface. The embryonization process of proliferating tissuewon’t go beyond the frame of the normal phenomenon untila certain amount of stem cells that are being reproducedand express embryonic antigens, reaches the critical mass,capable of becoming an object of reception by an organism’simmune system. Immunologic recognition is known to take place only inthat case when the cells, bearing heterologous antigens,make up a group of no less than 105 units [5], while thetissular conditions don’t impede it. The immune reaction thatfollows, imparts a malignant phenotype to the cells. It is thisvery moment that is crucial in the origin of neoplasms in allthe versions of tissue homeostasis’ disturbances. Proceeding on with the discussion of the postulate, let usrefer to the classic experiments conducted by B. Mintz toobtain allophenic chimeras [30]. The allophenic chimerism ofhealthy and full-value animals emerged in these experimentsas a result of inoculating into the blastocyst of mice of oneline the teratocarcinoma cells, derived from the animals ofanother line which had clear-cut phenotype distinctions fromthe first one in the form of black fur coloring as well as somebiochemical markers. In the mice produced from theblastocyst with the inoculated malignant tumor cells, thetissues and organs (right up to germinal ones) were built ofthe maternal organism cells and of the inoculated malignanttumor cells that lost their malignant phenotype and wereinvolved in normal embryogenesis. Teratocarcinomas are known to be obtained byinoculating the embryonic cells of an embryo of pre-implantation stages of its development into the so calledimmunologically preferential sites (anterior chamber of theeye, testes, subcapsular space of the kidney and others),wherein there are conditions of relative immunologicaltolerance. Manifestations of the immune reaction can beobserved in these sites too though in an impaired form [15]. 50
  51. 51. This immune reaction appears to be sufficient to impartmalignant phenotype features to the inoculated embryocells. 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 conditionswhere they are recognized by the immune system and areperceived by it as foreign ones. Before being used by B.Mintz in her experiments such teratocarcinoma cells havepreviously gone through 200 passages in the form of amalignant phenotype. But once they happened to get underthe conditions of a developing embryo they immediately losttheir malignancy. This suggests the fact that a malignancysign in this case is not associated with the stable genicaberrations, but is shaped by the environmental conditionswhere the main point is the presence or absence of anorganism’s immune reaction. Consequently, the embryocells being exposed to an organism’s immune reaction aretransformed into malignant ones, while the malignant cells,when getting under the conditions of normal embryogenesis(with no immune reaction present), become normal andcapable of being involved into the normal form-buildingprocess. In the midst of the 70-ies of the 20th century in theInstitute for Oncology Problems Acad. Sci. UkrSSR,investigations were carried out, the results of which wereconsonant with the experimental data, described by B.Mintz. When cultivating in diffusion chambers under theconditions of a healthy animals’ organism the Shwetserythromyelosis cells of rats, featured by non-differentiatedblast elements of myeloid and erythroid series, M.Baranovsky [3] observed their differentiation, that over 13days’ period of explantation in the red branch ofhemopoiesis was completed with the appearance of nuclearbaso-, polychromato- and oxyphile erythroblasts, but inmyeloid- monocytic branch of hemopoiesis – with theappearance of final functional (phagocyting macrophages)and morphologic (segmented granulocytes) forms. Thus,suffice was it to place leukemic cells, by means of a diffusionchamber under the conditions of isolation from theorganism’s immune system (it being represented by itscellular elements only) that their differentiation started to 51
  52. 52. occur. However the results of these experiments have neverbeen analyzed in this aspect. It will be expedient to mention here the findings of severalstudies that obtained evidences to the effect that malignanttumor cells, being inoculated into embryo, don’t give rise toneoplastic process. So, taking into consideration a generallyknown fact of the absence of spontaneous tumors in higheranimals at early stages of embryonic development, A.Savinska [8] cleared up the question as to whetherimplanted tumors would grow and develop in embryos indifferent periods of their intrauterine development. Sarcomacells’ suspension N16 in physiological solution or Ringersolution with carmine, added for control, was injectedthrough the uterus wall into rats’ embryos. 282 rats (2204embryos) were operated. 172 embryos (36 rats) werebrought to the end of the experiment. Sarcoma, inoculatedinto embryos at the last third of their intrauterinedevelopment, grew and developed both in newborn rats andin female-mothers. When inoculating sarcoma to embryos atthe first two thirds of their intrauterine development, tumorswere developed in females only. The newborn little ratsremained entirely healthy. The tumor failed to have taken onin anybody out of 19 embryos at this period of intrauterinedevelopment. Origination of tumors in all the cases ofpregnant females after inoculating the tumor material intoembryos 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 inanyone of 72 embryos that had undergone operation. Similar experiments were also conducted by B. Tokin andM. Aizupet [12]. Jensen sarcoma cells’ emulsion wasinjected into rats’ embryos (from 9 to 12 days of pregnancy).Little rats at the age of one week and adult animals servedfor control. Out of 172 fetuses born who were inoculated withtumor suspension in the period of their embryonicdevelopment, only 11 (6,4%) developed tumors. In controlanimals tumors have been taken on in 80% of cases. Tumors’ non-inoculability in embryos of the first two thirdsof pregnancy in experiments, conducted by A. Savinska, M.Whisson and B. Tokin, can be easily explained from thestandpoint of our postulate, that is, by undeveloped immune 52
  53. 53. system in embryos and, therefore, by the absence of itsaction upon tumor cells. The degree of success of malignant tumors implantationinto embryos of both young and adult animals coincides interms with the stages of formation of their immune system.Unfortunately, the state of the inoculated tumor material wasnot 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. 53
  54. 54. 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, onone hand, on how strong are the tumor cells’ potencies forthe progressive growth (as a rule, the less differentiated arethe cells, the higher are these potencies); on the other handit depends on how the character and the power of anorganism’s immune reaction in respect to the tumorcorrespond to that level of this reaction at which its strongesttumor-stimulating effect is observed. Summing up all the above-stated we come to thefollowing conclusion: irrespective of the nature and kindof carcinogenic factors as well as the circumstances oftheir action, a cellular conglomerate expressingembryonic antigens is shaped in an organism, sufficientin quantity for its reception by the organism’s immunesystem. It is the impact of the immune system effectorsupon this conglomerate that is responsible for itsgaining the properties of a malignant tumor and for afurther promotion of its growth. Thus, the specific organism’s immune reaction is unableto realize that kind of action, on which so much hope wasonce set. Under the natural conditions, it realizes just theopposite function, bringing about the formation of amalignant tumor process and promoting its development. Contemporary oncology has two alternative directions tosolve the problem of malignant tumor growth. Both the firstand the second ones are science-based and have aperspective for achieving favorable results. The main idea ofthe first one consists in striving to radically eliminate tumorcells wherever they may be [7]. Nowadays tremendousintellectual and material resources are turned to thedevelopment of this direction. Another direction is based onthe data, according to which malignant tumor cells retaintheir potential capacity for differentiation [11, 15, 33]; itprovides for the possibility to create conditions forretransformation of malignant cells into normal ones (it’s inan ideal case) or to achieve partial rise in the grade of tumor 54
  55. 55. cells’ differentiation, resulting in their malignancy decrease[14]. Advantages and attractiveness of such a direction areindisputable. It is this second pathway where we see theprospects for our ideas to be developed. We believe that the transformed cells’ capacity fordifferentiation may be realized, on condition, that thefactor impeding it, i.e., an organism’s immune reactionto tumor antigens, the embryonic ones in particular, hasbeen eliminated. Analyzing the problem of malignant tumor growth undersome other aspect, M.G. Baramiya arrived at the similarconclusion: to overcome the disintegrated (i.e. malignant)growth it’s necessary to induce and maintain in a tumor-hosta status of absolute immunologic unresponsiveness to thetransformed phenotype [2]. We regard all the above-stated as substantiation of afundamentally novel immunological approach to malignanttumors’ treatment, and the previous experimental findingscorroborate the productivity of this idea [16]. References1. Ageenko A.I, Yerchov V.S., Slavina Ye.G. Immunostimulation of tumor growth // New approaches to the issues of cancer immunology. – Tomsk: Izdatelstvo Tomskogo Universiteta, 1984.– S.30-40.2. Baramiya M.G. Carcinogenesis, aging and lifespan: potential of transformed cells and braking of aging (hypothesis) // Uspekhi sovremennoi biologii. – 1998. – 118. – P.421–439.3. Butenko Z.A., Baranovsky M.A., Naumenko O.I. Leukemic cells: origination, ultrastructure, differentiation. – Kiev: Naukova Dumka, 1984. – 216 p.4. Georgiyev G.P. Oncogenes //Vestnik AN SSSR. – 1984. – №5. – P.72–80.5. Deutschman G.I. The role of natural resistibility in an organisms reaction to the origin, growth and metastasize of tumors // Itogi nauki i techniki, VINITI. Oncology. – 1984. – 13. – P.46–97.6. Kokhan I. Immunology. – Kyiv – Toronto: Kobza,1994. – 416p. 55
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