Chekhun, V.F.

Experimental Oncology

Наукова електронна бібліотека періодичних видань НАН України (Vernadsky National Library of Ukraine)

Experimental Oncology ���� ��������� ����� ��ecem�er�� ���    In oncology it is continued to �e actual the pro�lem of working out the effective and selective modificators of action of conventional cytostatic means�� that has to enhance their antitumor effect as well to decline their toxic influence upon the normal tissue and organs. Among the variety of modificators of traditional antitu-mor therapy hyperthermia has a special place.  Hyper-thermia has �een known from Hippocrates time and turned attention of the medical scientists in the end of the 1�th century and received the principal new technical and �iological impact in ���-th of the past century.One of the initiators of the modern development of hyperthermia was the outstanding scientist-physicist Professor M. von Ardenne�� who has contri�ute much for develop this promise and effective method�� espe-cially as a whole �ody hyperthermic influence.Institute of Experimental Pathology�� Oncology and Radio�iology �IEPOR�� of National Academy of Sciences of Ukraine �Kiev�� has started to work in thе hyperthermia field since 1�7� owing to the proposition from famous scientific triumvirate: Prof. M. von Ardenne�� Prof. B. Pa-ton — President of National Academy of Sciences of Ukraine and Prof. R. Kavetsky — founder of IEPOR. At present the great interest is shown in Ukraine for hyper-thermia�� especially for the using of local heating in the treatment of patients with malignant tumors. Special care was given to the pro�lem of tumor microphysiology modulation with the aim to enhance the hyperthermia efficacy. The 1�th International Symposium on clinical Hyperthermia was held in Kiev on May�� 1��5.In January ���7 M. von Ardenne will �e 1�� years old. He was the promoter of the developing of the hyperthermia pro�lems in our Institute that allow to extend this promising method into com�ined treat-ment of oncological patients in Ukraine�� and pay show much respect to this great scientist the Editorial Board propose some material devoting to this date.Ardenne�� Manfred von��.�1.1��7����.�5.1��7Physicist and Cancer Researcher�� Prof. �r. h. c. mult1925–1926 two years study of physics�� chemistry and mathematics at the university of Berlin 1928–1945 erection and managing of a private re-search institute of electron physics in Berlin 1945 mem�er of the German “Reichsfors-chungsrat”��1945–1955 nuclear physicist in the USSR leader of a research institute for the development of industrial technologies for isotope separation in Sinop near Suchumi1955–1990 CEO of the “Manfred von Ardenne Re-search Institute” in �resden1956 Professor at the Technical University of �resden1957–1989 mem�er of the “Research Council of the G�R”1961 chairman of the “Society of Medical Electronics” of G�R1963–1989 vice chairman of the “Kultur�und-Frak-tion der Volkskammer der ��R”1965 mem�er of the “Internationalis Astonau-tica Academia” Pans1991–1997 CEO of the “Von Ardenne Institut fur Angewandte Medizimsche Forschung Gm�H”Main fields of research. Pioneer work in the field of radio- and television engineering�� of electron- and ion physics of �iomedical engineering�� first realization ANNIVERSARY PRofESSoR, DR. M. VoN ARDENNE (to thE 100 bIRthDAY of M. VoN ARDENNE)Exp Oncol ��������� 4�� �������ChRoNICLEReceived: October 20, 2006 *Correspondence: Е-mail: ceo@ardenne.de��� Experimental Oncology ���� ��������� ����� ��ecem�er��of an electronically wide�and amplifier�� development of the electron �eam oscilloscope of compact design�� first realization of the full-electronically television�� in-vention of the night vision equipment and X-ray image converter�� invention and development of the scanning electron microscope of high resolution�� R & � work at the electron microscope for Siemens�� methods to magnetically isotope separation�� electron �eam multy cham�er melting furnace�� plasma torch with finest plasma �eam of high density�� Oxygen Multistep Therapy and development of the systemic Cancer Multistep Therapy until the clinical application in con-ventional incura�le patients suffered from cancer with metastasis ���� patents in Germany and a�road.Publications. More than �� scientific �ooks�� �eside them “Funk-Ruf-Buch” �1��4���� “Verstärkermeßtechnik” �1������� “�ie Kathodenstrahlröhre” �1����� 1��� engi���� “Fernsehempfang” �1��5�� 1���� engi���� “Elektronen-Ü�ermikroskopie” �1�4��� 1�4� jap���� “Ta�ellen zur Ange-wandten Kernphysik” �1�5������ “Ta�ellen der Elektronen-physik�� lonenphysik und Ü�ermikroskopie” �1�5������ “Ta�ellen zur Angewandten Physik” �1������ 1�7����� “Kre�s-Mehrschntt-Therapie” �1���7�� 1�71���� “Sauer-stoff-Mehrschntt-Therapie” �1�7��� 1��1�� 1����� 1��7�� 1��� engi�� “Systemische Kre�s-Mehrschntt-Therapie” �1��7�� and more than 7�� further pu�lications.Awards. Lei�niz-Medal of Prussian Academy of Science �1�41���� State prize of USSR �1�47���� Stalin prize of USSR �1�5����� �r. rer. nat. h. �. �� University of Greifs-    wald �1�5����� National prizes of G�R �1�5���1���5���� �r. med. h. �. �� Medical Academy of �resden �1�7�����       �r. paed. h. �. �� �resden College of Education �1�������       Wilhelm-Ostwald-Medal of Saxon Academy of Science �1��5���� �iesel-medal of German Patent-Office �1������� Fnednch von Schiller Prize �1������� honorary citizen of city of �resden �1�����.WhoLE-boDY hYPERthERMIA IN thE-SCoPE of MANfRED VoN ARDENNE’S SYStEMIC CANCER MULtIStEP thERAPY (SCMt) (A short statement to the 100 birthday of M. von Ardenne (1907–1997))A. von Ardenne*B. Van Ardenne Institute of Applied Medical Research, Dresden, GermanyIn 1��4 Otto War�urg �1����1�7��� pu�lished his discovery of aero�e glycolysis of cancer cells [1]. In vitro he could proof and in 1���� confirm that tumor tissue in contrast to normal tissue has in presence of oxygen a prominent glycolytic meta�olism. Only retina and �rain tissue show partly glycolysis under aero�e conditions whereas in all other examined normal tis-sues no such process was o�served. War�urg consid-ered this peculiarity of cancer tissue as a “distur�ances of the respiration” [�]. Aero�e glycolysis of the tumor tissues causes the production of lactate�� which leads to a reduction of the extracellulary pH-value in the tumor tissue. This effect was o�served in human tumors�� too. This phenomenon can �e used to differentiate normal from tumor tissue [�]. The longstanding partnership �etween von Ardenne and War�urg was intensified in the �eginning of the sixties when von Ardenne develo-ped ideas for cancer treatment �ased on War�urgs experiments and findings of cancer cells growth. �iscussions and experimental investigations were intensified in such a way that War�urg convinced von Ardenne to quit physics and concentrate on medicine�� especially to focus on cancer research [4].fig. 1. Typical temperature-time course of systemic cancer multistep therapy �sCMT��As early as 1��5 Voegtiin o�served a decrease of the pH-value in tumor tissue upon application of glucose [5]. He measured the pH-value with a pH-electrode on sarcomas and carcinomas of rat. To our �est knowledge it was Naeslund�� who performed first measurements on human gynecological tumors under intravenous application of glucose in 1�5� [��].Von Ardenne and his team in �resden investigated the acidification of different tumor tissues also. They proposed an “in vivo theory of glycolytic meta�olism of tumors and their hyperacidification �y hypergly-cemia” and explored the dynamic of selective hyper acidification of tumors �y application of glucose [7�� �]. They discovered that no pH-decrease occurred dur-ing glucose infusion over many hours in the skeletal musculature and in the myocardium of rat [��� �]. Even in the �rain of rats under such conditions ��� mM��l�� occurred no considera�le pH-reduction [1�]. This and other o�servations lead to the conclusion that tumor tissue can �e selectively over acidified.Von Ardenne’s main goal — was to damage me-tastasis of unknown localizations in the �ody. Thus he had to ela�orate to what extend metastasis are over acidified. Experimental data lead to the conclusion that metastases even smaller then 1.5 mm� �approx 1��� cancer cells�� show a clear over acidification [11].“Classical” denaturants of proteins are acid and��or heat. This was the starting point for von Ardenne and his co-worker of many years Reitnauer to ela�orate on the synergy of hyperthermia and over acidification in 1���� in order to study cancer cell damage through thermo sensi�ilization due to low pH-values [1�]. They discove-red later on that this effect can even �e outperformed �y extreme whole-�ody hyperthermia ��ody core tempera-ture > 4�.5 °C��. Animal models provided experimental Experimental Oncology ���� ��������� ����� ��ecem�er�� ��1    data for selective tumor acidification. By increasing the temperature of the tumor to 4� to 4� °C the pH-value in such tissue decreased a�out �.5 pH-units [1�].Usually meta�olism is strongly activated during hyperthermia also in normal cells. A lack of oxygen and glucose as �asic elements for the ATP-synthesis would �e a disadvantage for normal cells in terms of their sta�ility. This is one of the main reasons that application of oxygen was implemented into the hy-perthermia cancer therapy also [14]. This results lead to the three main steps of systemic Cancer Multistep Therapy �sCMT���� which are:extreme whole-�ody hyperthermia+ induced hyperglycemia+ relative hyperoxemiaIn 1�74 in the sCMT it was suggested already a com�ination with cytostatics and radiotherapy [15]. The principle of the sCMT is represented �y those three steps with selective la�ilization of cancer tis-sue while sta�ilizing the healthy tissue. It should �e complemented �y further selective steps�� damaging the cancer tissues and sta�ilizing the normal tissues.Over a period of �5 years many methods were inves-tigated for systemic heating treatment of patients such as water �athes�� extra corporal heat or high-frequency hyperthermia. As the most promising method was found water-filtered infrared-A heat radiation �wIRA�� in terms of tolerance to human �odies simplicity and at the same time potency. In wIRA a�out two thirds of the irradiation energy is released in the corium and in deeper skin tis-sue. Once the heat radiation reaches the vessel �ed of the skin�� the �lood flow distri�utes the applied energy through the whole organism. This principle is similar to an outer �ody shell heating and allows a simple tem-perature control of the outer �ody shell and the �ody core. Such a whole-�ody hyperthermia system was realized in the whole �ody hyperthermia device called IRATHERM® ����. The temperature-time course of sCMT �Fig. 1�� shows that it is possi�le to reach a final temperature of over 4� °C and to apply a high dose of heat within �� minutes [1��].fig. 2. Individual evaluations related to diagnosis acc. To UICC criteria in different tumor entites; 5% confidence interval for nonP�-P� limitIn 1��� Manfred von Ardenne founded at his insti-tute in �resden a research clinic for evaluation of sCMT �uring a phase-I-study it was proofed that patients in the stage of conventional uncontrolla�le progression show a good systemic tolerance of sCMT with wIRA hyperthermia with only “minimal side effects” [17]. Five years later a research group at an university demon-strated in a phase-I��II study that this therapy “does not lead to any serious or sustained organ dysfunction and can therefore �e regarded as a safe therapy” [1�].In �resden’s sCMT clinic were given 4�� sGMT one-time treatments in com�ination with adapted chemotherapy to patients mostly with metastasis in the stage of uncontrolla�le progression �etween 1����� and 1����5. The mean �ody-core temperature had a value of 41.� °C ± �.� °C and the maximal �lood glucose level one of �7.� ± �.7 mM��l during the sixty minutes temperature plateau Fig. � shows the results of different tumor entities evaluated on the �ase of UICC criteria [1�].Furthermore sponsored �y the “German Cancer Aid” a prospective phase-I��II study was performed on patients with metastatic colorectal cancer at the University Hospital Virchow. Herein was tested a com-�ination of sCMT and chemotherapy protocol �folic acid + 5-Fluorouracil + Mitomycine-C��. The whole-�ody hyperthermia was realized �y application of wIRA�� where the �ody-core temperature increased to 41.� °С over ��� minutes as well as a 5�% enrichment of oxygen through inhalation. The induced hyperglycemia had a value of �� mM��l. �uring this study ten patients who did not responded to three cycles of chemotherapy were treated then with three cycles of sCMT plus the same chemotherapy. Three patients responded with partial remission �PR�� and in six patients progression of the disease �P��� was prevented. Furthermore despite the negative selection of patients in the control group almost the same results were o�tained in the progres-sion free survival in the control and-test group [��].�uring a pilot study 1� patients with metastasized adenocarcinomas ��reast�� n = 7�� ovarian�� n = 5�� colorectal�� n = 7�� were treated with sCMT plus che-motherapy. All patients were refractory to standard chemotherapy and lived in progression �P���. The result of this study showed that nine patients reached a PR and seven a No Chance �NC��. It was impossi�le to stop progression in four patients [�1].Two patients with refractory germ cell tumors were treated three times with sCMT plus chemotherapy �Ifosphamid + Car�oplatin + Etoposid��. In �oth cases a PR was reached after therapy completed [��].Besides the a�ove mentioned studies there are three extreme whole-�ody hyperthermia phase-II and two phase-III studies right now �������� on-going in Germany. All these studies are performed under induced hyperglycemia and relative hyperoxemia as well as com�ined with chemotherapy. They all follow the sCMT procedure.Manfred von Ardenne is without dou�t one of the most influential protagonist of hyperthermia in oncolo-��� Experimental Oncology ���� ��������� ����� ��ecem�er��gy�� who fought over 4� years for the vision that cancer cells can selectively �e damaged in com�ination with hyperthermia. Many groups are working today in the area of hyperthermia with the focus on oncology�� what is a proof for the rightness of his idea post mortem�� Manfred von Ardenne envisioned the sCMT in com�i-nation with chemotherapy and��or radiotherapy as an complementary method to conventional cancer thera-pies. In his opinion the �est timing for this therapy was an early stage of cancer�� prefera�ly perioperatively. This will �e hopefully proven in the future.REfERENCES1. Warburg ОН, Posener К, Negelein E. Uber den Stoff-wechsel der Karzinomzelle. Biochem Z 1924; 152: 309–44.2. Warburg ОН. The meatabolism of tumours. London: Constable, 1930; 326.3. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply and metabolic microenvironment of hu-man tumors. Cancer Res 1989; 49: 6449–65.4. Ardenne M. Ennnerungen, fortgeschneben. Dusseldorf: DrosteVerlag, 1997; 433.5. Voegtim С, Fitch RH, Kahler H. The influence of the parenteral administration of certain sugars on the pH of ma-lignant tumors. NatI Inst Health Bull 1935; 164: 1–14.6. Naeslund J Swenson KE. Investigations on the pH of malignant tumors in mice and humans after the administration of glucose. Gynecol Scand 1953; 32: 359–67.7. Ardenne Mv Rieger F. Mathematische in vivo Theone des Garungsstoffwechsels der Krebsgeschwulste. Z Naturforsch 1966; 21: 472–82.8. Reitnauer PG. Zur Methode der Ubersauerung von Tumoren in vivo. Z Med Labortech 1972; 13: 5–39.9. Ardenne M, Reitnauer PG, Rohde К. Zum pH-Ver-halten des Myokards und seiner Bedeutung fur Herzinfarkt- und Krebs-Mehrschntt-Therapie. Wiener klin Wschr 1972; 84: 47–54.10. Ardenne M, Reitftauer PG. pH-Messungen im Gehirn und Doppelattacke des Krebs-Merirschritt-Therapie-Konzep-tes. Klem Wschr 1970; 48: 658–68.11. Ardenne M, Chaplain RA, Reitnauer PG, Rohde К. pH-Messungen im Innern und in der Nahe optimiert ubersauerter Mikrometastasen verschiedener Große. Acta Biol Med Germ 1970; 25: 671–8.12. Ardenne M, Reitnauer PG. Selektive Krebszellensch-adigung durch Proteindenatunerung. Dtsch Gesundheitswesen 1968; 23: 1681–5, 1738–44.13. Ardenne M, Reitnauer PG. The amplification of the selective tumor acidification by local hyperthermia. Naturwis-senschaften 1978; 65: 159.14. Ardenne M, Lippmann HG. Uber Maßnahmen zur Vertraglichkeitserhohung der Doppelattacke des Krebs-Mehrschntt-Therapie-Konzeptes Verdopplung des O2-Partialdruckes in der Inspirationsluft bewirkt bedeutende Vergrößerung der Herz-Kreislauf-Reserven bei Hyperthermie bzw. Fieber mit hoher Temperatur-Zeit-Dosis. Dtsch Gesund-heitswesen 1970; 25: 1685.15. Ardenne M. Pnnzipien und Konzept 1974 der “Krebs-Mehrschntt-Therapie”. Radiobiol Radiother 1975; 1: 99–119.16. Wehner H, Ardenne A, Kaltofen S. Whole-body hy-perthermia with water-filtered infrared radiation technical-physical aspects and clinical experiences. Int J of Hyperthermia 2001; 17: 19–30.17. Steinhausen D, Mayer WK, Ardenne M. Evaluation of systemic tolerance of 42.0 °C infrared-A whole-body hyper-thermia in combination with hyperglycemia and hyperoxemia. A phase-I study. Strahlenther Onkol 1994; 170: 322–34.18. Kerner Т, Deja M, Ahlers O. Whole-body hyperthermia A secure procedure for patients with various malignancies? Intensive Care Med 1999; 25: 959–65.19. Ardenne M. Systemische Krebs-Mehrschntt-Therapie. Stuttgart Hippokrates Verlag, 1997: 195–209.20. Hildebrandt В, Drager J, Kerner Т. Whole-body hyperthermia in the scope of von Ardenne’s systemic cancer multistep therapy (sCMT) combined with chemotherapy in patients with metastatic colorectal cancer a phase I/II study. Int J of Hyperthermia 2004; 20: 317–3321. Bremer К, Меуег A, Lohmann R. Pilot study of whole-body hyperthermia combined with chemotherapy in patients with metastasised pretreated progressive breast, ovarian and colorectal carcinomas. Tumordiagnostik und Therapie 2001; 22: 115–20.22. Hildebrandt B, Wust P, Loffel J. Treatment of patients with refractory germ cell tumorswith whole-body hyperther-mia and chemotherapy. In ESHO 1999 Sept 1–4. Rotterdam, 1999: 66.

Anniversary professor, Dr. M. von Ardenne (to the 100 birthday of M. von Ardenne)

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Anniversary professor, Dr. M. von Ardenne (to the 100 birthday of M. von Ardenne)

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Наукова електронна бібліотека періодичних видань НАН України (Vernadsky National Library of Ukraine)