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1 77 DOI : /KPI Received : Accepted : Key Words: Mistletoe extracts, Anthroposophic Medicine, Phytotherapy, Complementary medicine The importance of clinical mistletoe cancer therapy and korean mistletoe pharmacopuncture preparation development and application possibility for oriental medicine Ok-Byung Choi Department of herbal medicine, Bio medicine Institute, Hoseo University ABSTRACT Objectives : Mistletoe extracts have been in use for around 85 years, predominantly in the area of cancer therapy. Today mistletoe preparations are among the most prescribed drugs in cancer medicine, thus constituting a standard biological therapy in the area of oncology. The purpose of this study is to analyze the practical implications of mistletoe cancer therapy, their clinical status, their preparation techniques and companies. Contents : Mistletoe therapy for cancer has been developed within the context of anthroposophical medicine. One major effect of mistletoe extract is that it stimulates the immune system and cancer defences. In Germany, a total of eight different mistletoe preparations are available, five developed by Anthroposophic Medicine and three evolved from research in phytotherapy. Therapy always consists of an introductory phase in order to test the patient s tolerance, find the right dosage and choose the most suitable preparation. This paper covers the background of mistletoe medical plant materials, mistletoe therapy for cancer, the anthroposophical medicine and clinical research, the practical regulation of treatment, preparation of mistletoe drugs. Result & suggestion : Mistletoe extracts are a complementary teratment of cancer, widely used in intergrative cancer care. The study of the integration of korean mistletoe extracts to oriental cancer medicine, its development and feasibility in Korea are urgently needed. The products, substances, compositions of european mistletoe drugs are very similar to those of oriental medicine theory. Applying the mistletoe cancer therapy and its preparation techniques to oriental medicine, the herbal acupuncture preparation should be modernized and korean mistletoe products are to be developed. To this end, government and herbal acupuncture society need to interact each other for the development of oriental mistletoe cancer medicine. I Loranthaceae Viscum Viscum album L. var. coloratum 30 1,500 corresponding author: ok-byung, CHOI, Institute of Basic Science, Dept. Herbal Medicine, Hoseo-University, 165 Sechul-ri, Baebang-eup, Asan-city, Chungnam, Korea (Tel choiob@hoseo.edu)

2 Loranthus tanakae Franch. & sav Viscum album L. Korthalsella japonica 80 Tab. 1 Tab.1 NK-cell phagocytose Leucocyte Cytotoxic complement Mutation Immunsystem Endorphine Tumorcell Survible time General condition Chemotherapy & Radiationtherapy side effects Tumor pain

3 79 II 1 Mistletoe Cancer Therapy Mistletoe Cancer Therapy Rudolf Steimer Ita Wegmann Mistletoe adjuvant palliative Rudolf Steiner Rudolf Steiner Loranthaceae Viscum album L. var. album Viscum album L. var. coloratum 3 Viscum album L. ssp. platyspermum

4 Viscum album L. ssp. laxum Viscum album L. ssp. abietis Rensch Viscin Viscin 1900 Viscin Einleger Glycogalactopentose Leprince Khwaja Muller Samuelsson g- Obatac Arginine 40%, proline 10% Glutamine, Asparagine, Tryptophane Ammonium sulfate chromatography VP-16-proteine Selaway 1942 Winterfeld, Dorle, Kronenthaler Viscotoxine 1958 Samuelsson Viscotoxine Viscotoxine polypeptide Viscotoxine 5KDa 6 A1, A2, A3, B, B2, 1-PS Viscotoxine Human Tumor Cell- Test necrotic effects Viscotoxine Tumor Cell Apotosis Viscotoxine Non-Toxic-Concentration 8~85nM NK- Cell Viscotoxine hemolytic effects Viscotoxine A1, A2, A3, B, I-PS, u-ps 6 Tab.2 Tab.2 phoratoxine phoratoxineb Krupe Bird Lectine Galactose 3 ML-, ML-, ML- ML- D-Galactose ML- N-Acetyl-D-Galactosamine ML- A-chaine B-chaine Lectine 60KDa Glycosilic polypeptidechain B-chain cytotoxic Ribosom-inactiv-A-chain Disulfate intracellurar ca 2+ chromatin free radical Apo2.7 cas-

5 81 pase3 phosphadidylserin-translocation, DNA-fragmentation Macrophage phagocyte Thymocyteproliferation stimulation T- Lymphocyte activation Lymphocyteproliferation stimulation CD8+-T-Lymphocyte cytotoxicity NK-Cell activation Histamin Polysaccharide, oilgosaccharide Arabinogalactane Gaultier Muller propyonylcholine Samuelsson g-aminobuttert Koch Ehrlich-Ascites-Carcinoma cellline Buehl Seeger 1966 Zschiesche phygocytose activity 1979 Bloksma Rentea Khwaja Ulrich Hulsen Hela cell L-cell Vester VP16 cytotoxic, anticancerotic, cytostatic effects VP16 300ng/ 1kg 50% Viscotoxine 0.8mg/kg Lectine Ehrlich-Ascites-Tumor Cell Lectine Lectine ribosomal protein Franz Lectine immunoglobuline phagocyte activation 1986 Hajto Lectine large granular lymphocyte NKcell Lectine Hajto Lectine ML- 1ng kg Tab. 3 Tab.3

6 Kaelin Koch intrapleural instilation Kiene controlled study Rudolf steiner 1 2 s.c, i.v, i.m cytokine T4/T8-Ratio NK-cell Apoptosis 6 Tab.4 Tab.4 1 Abnoba Viscum Lipid Micell colloidal solution Mix Viscum album L 3 Viscum album L. ssp. album Viscum album L. ssp. austriacum, 2 Eurixor Fr.E.Koch LectinMLI Viscum album L. ssp. abietis

7 83 3 Helixor Mix-system 7 MQ A , 0.1, 1, 5, 10, 20, 30, 50, Iscador Mix-system , Iscusin-ViscumIsorelPlenosol 7 Packaging 1 parameter ~2 1~ ~2 6 2 modulation 5 1~2 III Anthroposophic Medicine

8 Rudolf steiner Rudolf steiner Ita wegmann 80 3,000 long time adjuvant therapy non-toxic effects 1970 Abnoba, Iscador, Helixor, Eurixor, Iscusin, Vysorel Anthroposophic preparate phytomedical preparate Abnoba, Helixor, Iscador, Iscusin, Isorel Cefalektin, Eurixor, Lektinol Eurixor, Lektinol Lectine ML- 2 s.c Abnoba, Helixor, Iscador, Iscusin, Isorel 30 D Cefalektin, Eurixor, Lektinol Lectine ML- kg ML-

9 85 3 potenzierung process-standardization 5 4 Immunsystem modulation Cancer cell Apoptosis imflamation DNA Life quality Helixor Abnoba

10 IV 1. Goebel, T., Dorka, R.: Zur Morphologie und zur Zeitgestalt der Mistel (Viscum album L.). Tycho de Brahe-Verlag, Niefern Aymon, P.: Mistletoe in advanced Cancer. The Cancer Journal ; 123, Suppl Reinsch, P.: Neues Jahrbuch f r Pharmazie, Band 14, J.C. Mohr, Heidelberg Obata, Y.J.: agric. Chem. Soc. Japan ; Einleger, I., Fischer, J., Zellner, J.: Mh. Chem ; 44 : Leprince, M.: ibid ; 145 : Khwaja, T.A., Dias, C.B., Pentecost, S.: Recent Studies on the anticancer activities of Mistletoe (Viscum album) and its alkaloids. Oncology ; 43 : Havas, L.J.: Effects of colchicin and of Viscum album preparations upon germination of seeds and growth of seedlings. Nature (London) ; 139 : M ller, E.A., Anderer, F.A.: Chemical specificity of effector cell/tumor cell bridging by a Viscum album rhamnogalactouran enhancing cytotoxicity of human NK cells. Immunpharmacology ; 1 : Samuelsson, G.: Mistletoe Toxins. System. Zoology ; 22 : Obata, Y.J.: agric. Chem. Soc. Japan 1941 ; 17 : Franz, H.: Inhaltsstoffe der Mistel (Viscum album L.) als potentielle Arzneimittel. Pharmazie Suppl ; 40 : Selawry, O.S., Schwartz, M.R., Haar, H.: Tumor-inhibitory activity of products of Loranthaceae (mistletoe). Proc. amer. Assoc. Cancer Res ; 3 : Winterfeld, K., Kronenthaler, A.: Zur Chemie des blutdrucksenkenden Bestandteils der Mistel (Viscum album). III. Mitteilung. Arch. Pharmaz ; 280 : Giudici, A. M., Regente, M. C., Villalain, J., Pf uller, K., Pf uller, U., de la Canal, L.Mistletoe viscotoxins induce membrane permeabilization and spore death in phytopathogenic fungi. Physiol. Plant., 2004 : 121 : Tabiasco, J., Pont, F., Fournie, J. J., Vercellone, A. Mistletoe viscotoxins increase natural killer cell-mediated cytotoxicity. Eur. J. Biochem., 2002 ; 269: Andersson K.E., Johannsson M. Effect of viscotoxin on rabbit heart and aorta, and on frog skeletal muscle. Eur. J. Pharmacol ; 23 : Schaller G., Urech, K., Giannattasio, M. Cytotoxicity of different viscotoxins and

11 87 extracts from the European subspecies of Viscum album L. Phytother. Res., 1996 ; 10: Thunberg, E.: Phoratoxin B, a toxic protein from the mistletoe Phoradendron tomentosum sp. macrophyllum. Acta Pharmac. suecica ; 20 : Boie, D.: Arbeitsbericht Nr. Verein f r Leuk - mie- und Krebstherapie, Rosenfeld 1977 ; Franz, H., Ziska, P., Kindt, A.: Isolation and properties of three lectins from misteltoe (Viscum album L.). Biochemical Journal ; 195 : Franz, H., Ziska, P., Kindt, A.: A simple method for the preparation of the two different chains of the mistletoe lectin I. Lectins- Biology, Biochemistry, Clinical Biochemistry 2. Walter de Gruyter & Co., Berlin - New York Agapov, I. I., Tonevitsky, A. G., Moisenovich, M. M., Maluchenko, N. V., Weyhenmeyer, R., Kirpichnikov, M. P. Mistletoe lectin dissociates into catalytic and binding subunits before translocation across the membrane to the cytoplasm. FEBS Lett., 1999b : 452: Bantel, H., Engels, I., H., Voelter, W., Schulze- Osthoff, K., Wesselborg, S. Mistletoe lectin activates caspase-8/flice independently of death receptor signaling and en hances anticancer drug-induced apoptosis. Cancer Res., 1999 ; 59: Kienle, G. S., Kiene, H. Die Mistel in der Onkologie - Fakten und konzeptionelle Grundlagen. Schattauer Verlag, Stuttgart, New York M ller, J.A.: Arch. Pharmaz ; 270 : Samuelsson, G.: Phytochemical and Pharmacological Studies on Viscum album L. - III. Isolation of a hypotensive substance: Gammaaminobutyric acid. Svensk. farmac. Tidskr ; 63 : Chernov, W.A.: Trud. Akad. med. Nauk SSSR, Vopr. onkol ; Buhl, S.A.: Zur Wirkung von Iscador und eines aus diesem gez chteten Bakterienstammes auf einen M usetumor und den tumortragenden Organismus. Dissertation, Heidelberg Zschiesche, W.: Die Wirkung von Iscador auf Phagocytoseaktivit t des reticulohistiocyt ren Systems. Mber. dtsch. Akad. Wiss ; 8 : Bloksma, N., van Dijk, H., Korst, P., Willers, M.: Cellular and humoral adjuvant activity of a mistletoe extract. Immunobiol ; 156 : Rentea, R., Lyon, E., Hunter, R.: Biologic Properties of Iscador : A Viscum album Preparation. I. Hyperplasia of the Thymic Cortex and Accelerated Regeneration of Hematopoietic Cells following X-Irradiation. Lab. Invest ; 44 : Khwaja, T.A:, Varven, J.C., Pentecost, S., Pande, H.: Isolation of bilogically active alcaloids from Korean mistletoe viscum album, coloratum. Experentia (Basel) ; 36 : H lsen, H., Mechelke, F.: The influence of a mistletoe preparation on suspension cell cultures of human leukemia and human myeloma cells. Arzneimittelforschung ; 32 : Vester, F., Bohne, L., El - Fouly, M.: Zur Kenntnis der Inhaltsstoffe von Viscum album. IV: Biologisches Verhalten einzelner Proteinfraktionen. Hoppe-Seyler s Z. Physiol. Chem ; 349 : Stirpe, F., Legg, R.F., Onyon, L.J., Ziska, P., Franz, H.: Inhibition of protein synthesis by a toxic lectin from Viscum album L. (mistletoe). Biochem. J ; 190 : Franz, H., Haustein, B., Luther, P., Kuropka, U., Kindt, A.: Isolierung und Charakterisierung von Inhaltsstoffen der Mistel. Acta biol. med.

12 german ; 36 : Koch, Fr.E.: Experimentelle Untersuchungen ber entz ndungs- und nekroseerzeugende Wirkung von Viscum album. Zeitschr. Ges. exper. Medizin 1938 ; 103 : Stumpf, C. und Schietzel, M.: Intrapleurale Instillation eines Mistelextraktes aus Viscum album (L.) zur Behandlung maligner Pleuraerg sse. Tumordiagn. u. Ther ; 15 : Kiene, H.: Klinische Studien zur Misteltherapie karzinomat ser Erkrankungen - Eine bersicht. Sonderdruck aus: Therapeutikon ; 3 : Table 1. Human activity and functional mechanism of Mstletoe Human Activity Tumor Growth Inhibition Immunmodulation DNA & Immunprotection Life - Quality Functional Mechanism - direct : Dosage dependent cytotoxicity(proteinsynt hesis, apoptosis induction) - indirect : Tumor angiogenesis inhibition - Cytokine increase - Immunological effectercell increase - Lymphocyte : DNA-stability DNA-repair - Immunsupressive Effects of chemotherapy - -Endorphine increase Table 2. 50% Toxicity Concentration of various Viscotoxine type an Yoshida- Sarcoma Cells Viscotoxine Type ED50 A A A B 4.58 I-PS 0.44 U-S 4.04 Table 3. The pharmaceutical effects in the cancer cells and immunsystem by mistletoe ingredients Ingredients Substances Effect on Cancer cell Effect on Immunsystem ML Glycoproteins -Ribosomen Protein synthesis -Cell Apoptosis activation TNF - IL-1, IL-2, IL-6 increase Viscotoxine Polypeptide -Cell Cytotoxicity by membrane lyse -Macrophage activation -Granulocyte cytotoxicity Peptide 5000Da Peptide -Cytotoxicity -Cytotoxic Macrophage activation Arabinogalactane, Galacturonane Oligo-& polysaccharide -T-helpercell activation -NK-cell activation Quercetin derivate Flavonoids -Apoptosis induction -Antioxidativ & protective effects

13 89 Table 4. Various european mistletoe preparation and specification for cancer therapy Name Company Medicinal type Sort Production method Ampulling dosage Therapy dosage Application Abnoba Viscum Abnoba Heilmittel GmbH 1972 Anthroposophic & Homeopathic Medicine A, Ac, Am, B, C, F, M, P, Qu Liposomal press extraction 20, 2, 0.2, 0.02 / and D6, D10, D20, D30/ Therapy start : 0.02 /1 week 3 time inject later : individual high dosage inject -Cancer therapy for malignant & benign -Cancer Recidiv -Immun stimulation Therapy start : 0.1mg Eurixor Biosyn Arzneimitt el GmbH 1990 Phyto therapy Po 1 / Fresh-waterextraction ML-I-standardization i.c/1week 1~2time inject later : 1 i.c, s.c or i.v/individual inject maintenance : 1 / -Cancer palliative therapy 1week 1~2time inject Therapy start : 0.01, -Cancer therapy 0.1, 1 s.c/1week for malignant & Helixor Helixor Heilmittel GmbH 1972 Anthroposophic Medicine A, M, P Fresh-waterpressing 0.01, 0.1, 1, 5, 10, 20, 30, 50 in 1 & 100 in 2 2~3time inject later : individual high dosage inject maintenance : regular benign -Cancer Recidiv -Immun stimulation high or low dosage -Bone marrow inject activation Iscador Weleda AG 1920 Anthroposophic Medicine P, M, Qu, u water-extracts with special mineral fermentation , 0.001, 0.01, 0.1, 1, 10, 20 / without Mineral -0.01, 0.1, 1, 10, 20 / with Mineral Therapy start : series- 0( ) 1week s.c 3time s.c inject later : individual high dosage inject -Cancer therapy for malignant & benign -Cancer Recidiv -Immun stimulation A: Abies, Ac: Acer, Am: Amygdalus, B: Betula, C: crataegus, M: Malus, P: Pinus, Po: Populus, Qu: Quercus, S: Salix, T: Tilia, U: Ulmus, i.c: intracutane, i.v: intravenos, s.c: subcutane

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경락경혈학회지 Vol.27, No.1, pp.87 106, 2010 Journal of Meridian & Acupoint Dept. of 1 Meridian & Acupoint, 3 Acupuncture & Moxibustion, College of Oriental Medicine, Daejeon University 2 Division of Clinical