The use of the mistletoe plant as a drug has a long tradition which traces back to the fourth century BC. Throughout the centuries this evergreen half-parasite which is mostly associated Christmas and Santa, was used by healthcare professionals and doctors for menstrual complaints, epilepsy, ulcers, cardiac insufficiency, high blood pressure and oedemas [1,2]. The white-berried mistletoe (Viscum album L) only entered cancer setting as alternative and complementary cancer medicine at the beginning of the 20th century through Rudolf Steiner (1861 – 1925), the founder of Anthroposophic Medicine[3]. In 1916, he first mentioned the therapeutic possibilities of mistletoe extracts in the cancer setting.
How does the Mistletoe Therapy help with cancer?
Mistletoe therapy acts on many levels: On the one hand, it boosts the immune system by multiplying and activating the immune cells. On the other, mistletoe therapy can induce apoptosis (the process of natural cell death) in tumour cells, which results in the inhibition of tumour growth. Healthy tissue is not adversely affected by this. On the contrary, immune cells and other healthy cells are protected against further injury, e.g. damage caused by cytostatic drugs. Patients report that mistletoe therapy significantly improves their quality of life.
Actions:
• Improvement of general condition and quality of life through
• Increased performance and vigour, less fatigue
• Normalised body rhythms including body temperature, sleep and digestion
• Increased appetite
• Reduced nausea and vomiting
• Greater emotional well-being
• Reduced depression and anxiety
• Reduction of adverse reactions to conventional therapies (e.g. chemo- or radiotherapy), in particular, cancer-related fatigue
• Alleviation of tumour-related pain
This mode of action makes mistletoe therapy a key supplement to standard oncological therapy.
Basic research results indicate that medicinal mistletoe may stimulate the immune system to fight cancer cells. Cytotoxic effects on tumour cells have been observed in animal models [4,5]. One study data showed that mistletoe injections can attenuate airway inflammation and eosinophil infiltration in different types of cancers.[6] Studies in human beings suggest that the use of mistletoe extract alongside appropriate chemotherapy and radiotherapy may improve their tolerability by reducing their side effects and increasing quality of life, including in pancreatic [7,8], lung[9], colorectal[10], and breast cancers[11]. A few studies indicate a possible positive effect on survival [7,12-14], although no significant survival effects were found for patients with metastatic colorectal cancer[15], melanoma[16], or head and neck cancer [17], and further studies are required to confirm these findings. Other preliminary studies suggest that intravesical mistletoe extract is safe and well-tolerated in patients with nonmuscle invasive bladder cancer[18], and that mistletoe extract injection may be efficacious as chemical pleurodesis in patients with malignant pleural effusion[19]. With regards, to possible interaction with chemotherapy, in two studies with 5-year follow-ups of breast cancer patients, mistletoe therapy did not appear to have a negative impact on chemotherapy efficacy[11] and appeared to contribute to reducing disease/therapy-related signs and symptoms (e.g. mucositis, fatigue, pain, headache)[20]. The addition of mistletoe extracts in patients with advanced solid tumours allowed for higher gemcitabine doses to be used without apparent pharmacokinetic interactions[21].
Mechanisms of mistletoe extract action (summary)
Mistletoe extracts contain biologically active substances such as glycoproteins, especially mistletoe lectines I, II and II (ML I, ML II, ML III)[22], polypeptide (e.g. viscotoxins[23-25]), peptides, amino acids, oligo- and polysaccharids[26-27]. Other molecules have also shown to have possibly beneficial properties, such as enzymes, sulphurous compounds, fats, phytosterols, triterpenes[28-31], flavonoids, phenylpropanes, lignans, alkaloids, minerals, micronutrients and other proteins[32,33].
Mistletoe lectins are the most investigated component. Their cytotoxic effects are partially due to ribosome- inactivating properties and induction of apoptosis[34 (“cell suicide”). In-vitro studies have shown that mistletoe lectins increase TNFα, IL-1, IL-2, and IL-6 cytokine secretion, stimulate immune-cell phagocytosis, induce macrophage cytotoxicity, and enhance cytotoxicity on cancer cells[35]. In lymphoblastic leukaemia cells, mistletoe extracts stimulate dendritic cell maturation and activation36 and induce dose-dependent apoptosis through caspase-8 and -9 dependent pathways[37]. Studies performed in animal models have shown that apoptotic induction[37] produced by mistletoe extracts rich in triterpenes was greater, and also that these extracts improved efficacy against malignant melanoma when compared with conventional extracts, which reduce tumour angiogenesis[38]. Another component called Viscotoxins may also have tumour-inhibiting and immune-stimulating properties[39]. However, the pro and anti-proliferative effects produced by mistletoe extracts produced depended on dose[40]. Mistletoe- induced immune stimulation may explain physical improvements that contribute to increased quality of life in cancer patients[34].
Mistletoe extracts can be injected under the skin or infused directly via IV. Here at WMG we specialise in the delivery of this special extract via intravenous infusion (infused by slow drip directly into the blood stream) Although this administration route is off-label, it is completely safe and widely used.
IMPORTANT NOTE: The mistletoe extract does need a medical prescription and the therapy does require medical supervision. Do not trust any product available online without a medical prescription.
Our lead consultant – Dr Kloppenburg Vieth offers complementary initial calls for all integrated infusion therapies.
1. Kienle G., Kiene H. (2003) Verträglichkeit, Nebenwirkungen, Überempfindlichkeitsreaktionen, Toxizität. In: Kienle G., Kiene H., Die Mistel in der Onkologie. Fakten und konzeptionelle Grundlagen. Stuttgart: Schattauer 2003, 591–607.
2. Büssing A: Biological and pharmacological properties of Viscum album L. In Büssing A (Ed): Mistletoe – The Genus Viscum. Harwood Academic Publishers, Amsterdam, 124-182 (2000).
3. Kienle GS, Kiene H, Albonico HU: Anthroposophic Medicine: Effectiveness, Utility, Costs, Safety. Stuttgart, New York: Schattauer Verlag; 2006.
4. Struh CM, Jager S, Schempp CM, et al. A novel triterpene extract from mistletoe induces rapid apoptosis in murine B16.F10 melanoma cells. Phytother Res. Oct 2012;26(10):1507-1512. doi: 10.1002/ptr.4604
5. Beuth J, Ko HL, Schneider H, et al. Intratumoral application of standardized mistletoe extracts down regulates tumor weight via decreased cell proliferation, increased apoptosis and necrosis in a murine model. Anticancer Res. Nov-Dec 2006;26(6B):4451-4456.
6. Shen JJ, Chiang MS, Kuo ML, et al. Partially purified extract and viscolin from Viscum coloratum attenuate airway inflammation and eosinophil infiltration in ovalbumin-sensitized mice. J Ethnopharmacol. Jun 1 2011;135(3): 646-653. doi: 10.1016/j.jep.2011.03.065
7. Troger W, Galun D, Reif M, et al. Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: a randomised clinical trial on overall survival. Eur J Cancer. Dec 2013;49(18):3788-3797. doi: 10.1016/j.ejca.2013.06.043
8. Troger W, Galun D, Reif M, et al. Quality of life of patients with advanced pancreatic cancer during treatment with mistletoe: a randomized controlled trial. Dtsch Arztebl Int. Jul 21 2014;111(29-30):493-502, 433 p following 502.
9. Bar-Sela G, Wollner M, Hammer L, et al. Mistletoe as complementary treatment in patients with advanced non- small- cell lung cancer treated with carboplatin-based combinations: a randomised phase II study. Eur J Cancer. Mar 2013;49(5):1058-1064. doi: 10.1016/j.ejca.2012.11.007
10. Friedel WE, Matthes H, Bock PR, et al. Systematic evaluation of the clinical effects of supportive mistletoe treatment within chemo- and/or radiotherapy protocols and long-term mistletoe application in nonmetastatic colorectal carcinoma: multicenter, controlled, observational cohort study. J Soc Integr Oncol. Fall 2009;7(4): 137-145.
11. Troger W, Zdrale Z, Stankovic N, et al. Five-year follow-up of patients with early stage breast cancer after a randomized study comparing additional treatment with Viscum album (L.) extract to chemotherapy alone. Breast Cancer (Auckl). 2012;6:173-180. doi: 10.4137/bcbcr.s10558
12. Ostermann T, Raak C, Bussing A. Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review. BMC Cancer. 2009;9:451. doi: 10.1186/1471-2407-9-451
13. Grossarth-Maticek R, Kiene H, Baumgartner SM, et al. Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern Ther Health Med. May-Jun 2001;7(3):57-66, 68-72, 74-56 passim.
14. Grossarth-Maticek R, Ziegler R. Randomised and non-randomised prospective controlled cohort studies in matched- pair design for the long-term therapy of breast cancer patients with a mistletoe preparation (Iscador): a re-analysis. Eur J Med Res. Nov 30 2006;11(11):485-495.
15. Bar-Sela G, Haim N. Abnoba-viscum (mistletoe extract) in metastatic colorectal carcinoma resistant to 5- fluorouracil and leucovorin-based chemotherapy. Med Oncol. 2004;21(3):251-254. doi: 10.1385/MO:21:3:251
16. Kleeberg UR, Suciu S, Brocker EB, et al. Final results of the EORTC 18871/DKG 80-1 randomised phase III trial. rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer. Feb 2004;40(3): 390-402.
17. Steuer-Vogt MK, Bonkowsky V, Ambrosch P, et al. The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. Eur J Cancer. Jan 2001;37(1):23-31.
18. Rose A, El-Leithy T, vom Dorp F, et al. Mistletoe Plant Extract in Patients with Nonmuscle Invasive Bladder Cancer: Results of a Phase Ib/IIa Single Group Dose Escalation Study. J Urol. Oct 2015;194(4):939-943.
19. Cho JS, Na KJ, Lee Y, et al. Chemical Pleurodesis Using Mistletoe Extraction (ABNOVAviscum((R)) Injection) for Ann Thorac Cardiovasc Surg. 2016;22(1):20-26.
20. Beuth J, Schneider B, Schierholz JM. Impact of complementary treatment of breast cancer patients with standardized mistletoe extract during aftercare: a controlled multicenter comparative epidemiological cohort study. Anticancer Res. Jan-Feb 2008;28(1b):523-527.
21. Mansky PJ, Wallerstedt DB, Sannes TS, et al. NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors. Evid Based Complement Alternat Med. 2013;2013:964592. doi: 10.1155/2013/964592
22. Franz H, Ziska P, Kindt A: Isolation and properties of three lectins from mistletoe ( Viscum album L.). Biochemical Journal 1981, 195:481-484.
23. Winterfeld K, Bijnen AB: Viscotoxin, ein neuer Inhaltsstoff der Mistel ( Viscum album L.). Liebigs Ann Chem 1948, 561:107- 115.
24. Urech K, Scher JM, Hostanska K, Becker H: Apoptosis inducing activity of viscin, a lipophilic extract from Viscum album L. Journal of Pharmacy and Pharmacology 2005, 57 101-109.
25. Winterfeld K, Kronenthaler A: Zur Chemie des blutdrucksenkenden Bestandteils der Mistel. (Viscum album). Arch Pharm 1942, 280:103-115.
26. Mueller EA, Anderer FA: A Viscum album oligosaccharide activating human natural cytotoxicity is an interferon gamma inducer. Cancer Immunol Immunother 1990, 32:221-227.
27. Klett CY, Anderer FA: Activation of natural killer cell cytotoxicity of human blood monocytes by a low molecular weight component from Viscum album extract. Arzneimittel-Forschung/Drug Research 1989, 39 (II)(12):1580-1585.
28. Struh CM, Jager S, Kersten A, Schempp CM, Scheffler A, Martin SF: Triterpenoids amplify antitumoural effects of mistletoe extracts on murine B16.f10 melanoma in vivo. PLoS One 2013, 8(4):e62168.
29. Delebinski CI, Jaeger S, Kemnitz-Hassanin K, Henze G, Lode HN, Seifert GJ: A new development of triterpene acid- containing extracts from Viscum album L. displays synergistic induction of apoptosis in acute lymphoblastic leukaemia. Cell Prolif 2012, 45(2):176-187.
30. Kleinsimon S, Kauczor G, Jaeger S, Eggert A, Seifert G, Delebinski C: ViscumTT induces apoptosis and alters IAP expression in osteosarcoma in vitro and has synergistic action when combined with different chemotherapeutic drugs. BMC Complement Altern Med 2017, 17(1):26.
31. Twardziok M, Kleinsimon S, Rolff J, Jager S, Eggert A, Seifert G, Delebinski CI: Multiple Active Compounds from Viscum album L. Synergistically Converge to Promote Apoptosis in Ewing Sarcoma. PLoS One 2016, 11(9):e0159749.
32. Saller R., Kramer S., Iten F., Melzer J. (2005) Unerwünschte Wirkungen der Misteltherapie bei Tumourpatien- ten – Eine systematische Übersicht. In: Scheer R., Bauer R., Becker H., Fintelmann V., Kemper F. H., Schil- cher H. (Hrsg.), Fortschritte in der Misteltherapie: Aktueller Stand der Forschung und klinische Anwendung. Essen: KVC Verlag 2005, 367–403.
33. Urech et al.: Triterpenes of mistletoe (VIscum album) in the “bird-lime” Viscin and its antiprolifertive activity. In Scheer R et al (Ed): Fortschritte in Der Misteltherapie. KVC Verlag, Essen, 133-144 (2005)
34. Melzer J, Iten F, Hostanska K, et al. Efficacy and safety of mistletoe preparations (Viscum album) for patients with cancer diseases. A systematic review. Forsch Komplementmed. Aug 2009;16(4):217-226. doi: 10.1159/000226249
35. Goebell PJ, Otto T, Suhr J, et al. Evaluation of an unconventional treatment modality with mistletoe lectin to prevent recurrence of superficial bladder cancer: a randomized phase II trial. J Urol. Jul 2002;168(1):72-75.
36. Elluru SR, Duong van Huyen JP, Delignat S, et al. Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer. BMC Cancer. 2008;8:161. doi: 10.1186/1471-2407-8-161
37. Delebinski CI, Jaeger S, Kemnitz-Hassanin K, et al. A new development of triterpene acid-containing extracts from Viscum album L. displays synergistic induction of apoptosis in acute lymphoblastic leukaemia. Cell Prolif. Apr 2012;45(2):176-187. doi: 10.1111/j.1365-2184.2011.00801.
38. Struh CM, Jager S, Kersten A, et al. Triterpenoids amplify anti-tumoral effects of mistletoe extracts on murine B16.f10 melanoma in vivo. PLoS One. 2013;8(4):e62168. doi: 10.1371/journal.pone.0062168
39. Kleijnen J, Knipschild P. Mistletoe treatment for cancer review of controlled trials in humans. Phytomedicine. Dec 1994;1(3):255-260. doi: 10.1016/S0944-7113(11)80073-5
40. Lyu SY, Park WB. Effects of Korean mistletoe lectin (Viscum album coloratum) on proliferation and cytokine expression in human peripheral blood mononuclear cells and T-lymphocytes. Arch Pharm Res. Oct 2007;30(10): 1252-1264.
41. Weissenstein U, Kunz M, Urech K, et al. Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro. BMC Complement Altern Med.2014;14:6. doi: 10.1186/1472-6882-14-6
42. Engdal S, Nilsen OG. In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patients.Phytother Res. Jul 2009;23(7):906-912. doi: 10.1002/ptr.2750
43. Huber R, Eisenbraun J, Miletzki B, et al. Pharmacokinetics of natural mistletoe lectins after subcutaneous injection.Eur J Clin Pharmacol. Sep 2010;66(9):889-897. doi: 10.1007/s00228-010-0830-5
44. Schad F, Atxner J, Buchwald D, et al. Intratumoral Mistletoe (Viscum album L) Therapy in Patients WithUnresectable Pancreas Carcinoma: A Retrospective Analysis. Integr Cancer Ther. Jul 2014;13(4):332-340.
45. Steele ML, Axtner J, Happe A, et al. Use and safety of intratumoral application of European mistletoe (Viscumalbum L) preparations in Oncology. Integr Cancer Ther. Mar 2015;14(2):140-148.
46. Bussing A, Stumpf C, Troger W, et al. Course of mitogen-stimulated T lymphocytes in cancer patients treated withViscum album extracts. Anticancer Res. Jul-Aug 2007;27(4C):2903-2910.
47. Steele ML, Axtner J, Happe A, et al. Adverse Drug Reactions and Expected Effects to Therapy with SubcutaneousMistletoe Extracts (Viscum album L.) in Cancer Patients. Evid Based Complement Alternat
Med.2014;2014:724258. doi: 10.1155/2014/724258 Related articles:
48. Huber R, Ludtke R, Klassen M, et al. Effects of a mistletoe preparation with defined lectin content on chronichepatitis C: an individually controlled cohort study. Eur J Med Res. Sep 28 2001;6(9):399-405.
49. Horneber MA, Bueschel G, Huber R, et al. Mistletoe therapy in oncology. Cochrane Database Syst Rev.2008(2):CD003297. doi: 10.1002/14651858.CD003297.pub2
50. Bar-Sela G. White-berry mistletoe (Viscum album L.) as complementary treatment in cancer: Does it help? Eur JIntegr Med. 2011;3:e55-e62.
51. de Giorgio A, Stebbing J. Mistletoe: for cancer or just for Christmas? Lancet Oncol. Dec 2013;14(13):1264-1265.doi: 10.1016/s1470-2045(13)70560-6
52. Ernst E. Herbal medicinal products during pregnancy: are they safe? BJOG. Mar 2002;109(3):227-235.
53. Evens ZN, Stellpflug SJ. Holiday plants with toxic misconceptions. West J Emerg Med. Dec 2012;13(6):538-542.doi: 10.5811/westjem.2012.8.12572
54. Rosell S, Samuelsson G. Effect of mistletoe viscotoxin and phoratoxin on blood circulation. Toxicon. Aug1966;4(2):107-110.
55. Finall AI, McIntosh SA, Thompson WD. Subcutaneous inflammation mimicking metastatic malignancy induced by injection of mistletoe extract. BMJ. Dec 23 2006;333(7582):1293-1294. doi: 10.1136/bmj.39044.460023.BE 56. Hall AH, Spoerke DG, Rumack BH. Assessing mistletoe toxicity. Ann Emerg Med. Nov 1986;15(11):1320 1323.
57. Kim HJ, Kim H, Ahn JH, et al. Liver injury induced by herbal extracts containing mistletoe and kudzu. J Altern Complement Med. Mar 2015;21(3):180-185.
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