Mistletoe Extracts (PDQ®)–Health Professional Version

This cancer information summary provides an overview of the use of mistletoe as a treatment for people with cancer. The summary includes a brief history of mistletoe research, the results of clinical trials, and possible side effects of mistletoe use.

This summary contains the following key information:

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

Mistletoe, a semiparasitic plant, holds interest as a potential anticancer agent because extracts derived from it have been shown to kill cancer cells in vitro [1-10] to down-regulate central genes involved in tumor progression, malignancy, and cell migration and invasion, such as TGF-beta and matrix-metalloproteinases.[11,12] Mistletoe extracts have been shown to do the following:[10-31]

Three components of mistletoe, namely viscotoxins, polysaccharides, and lectins, may be responsible for these effects.[10,13-15,19-21,23-25,32-39] Viscotoxins are small proteins that exhibit cell-killing activity and possible immune system–stimulating activity.[1,6,20,21,40,41] Lectins are complex molecules made of both protein and carbohydrates that are capable of binding to the outside of cells (e.g., immune system cells) and inducing biochemical changes in them.[10,42-45]

In view of mistletoe’s ability to stimulate the immune system, it has been classified as a type of biological response modifier.[42] Biological response modifiers constitute a diverse group of biological molecules that have been used individually, or in combination with other agents, to treat cancer or to lessen the side effects of anticancer drugs. Mistletoe extracts have been demonstrated in preclinical settings to have other mechanisms of action, such as antiangiogenesis.[29]

Preparations from mistletoe extracts are most frequently used in the treatment of cancer patients in German-speaking countries.[46] Commercially available extracts are marketed under a variety of brand names, including Iscador (see explanation of suffixes below), Eurixor, Helixor, Isorel, Iscucin, Plenosol, and abnobaVISCUM. Some extracts are marketed under more than one name. Iscador, Isorel, and Plenosol are also sold as Iscar, Vysorel, and Lektinol, respectively. All of these products are prepared from Viscum album (Loranthaceae) (Viscum album L. or European mistletoe). They are not sold as a drug in the United States. Eurixor, Isorel, and Vysorel are no longer commercially available.

In addition to European mistletoe, extracts from a type of Korean mistletoe (Viscum album var. coloratum [Kom.] Ohwi) have demonstrated in vitro and in vivo cytotoxicity in laboratory studies.[47-51]

Mistletoe grows on several types of trees, and the chemical composition of extracts derived from it depends on the following:[8,43,52-55]

Mistletoe extracts are prepared as aqueous solutions or solutions of water and alcohol, and they can be fermented or unfermented.[4,6,22,52,53,56-59] Some extracts are prepared according to homeopathic principles, and others are not. Accordingly, as homeopathic preparations, they are typically not chemically standardized extracts.[10,60] In addition, the commercial products can be subdivided according to the species of host tree, which is typically indicated in the product name by a suffix letter. Iscador, a fermented aqueous extract of Viscum album L. that is prepared as a homeopathic drug, is marketed as one of the following:[57]

Helixor, an unfermented aqueous extract of Viscum album L. that is standardized by its biological effect on human leukemia cells in vitro, is marketed as one of the following:[57]

Eurixor (which is no longer commercially available), an unfermented aqueous extract of Viscum album L. harvested from poplar trees, is reportedly standardized to contain a specific amount of one of mistletoe’s lectins (i.e., the lectin ML-1).[57] For more information, see the History section. Some proponents contend the choice of extract should depend on the type of tumor and the sex of the patient.[55,57,61,62]

A recombinant ML-1 from Escherichia coli bacteria known as rViscumin or aviscumine has been studied in the laboratory and in phase I clinical trials. Because this is not an extract of mistletoe, it is out of the purview of this summary.[63]

Mistletoe extracts are usually given by subcutaneous injection, although administration by other routes (i.e., oral, intrapleural, intratumoral, and intravenous) has been described.[19,22-26,39,43,55,57,60,64-70] In most reported studies, subcutaneous injections were given 2 to 3 times a week, but the overall duration of treatment varied considerably.

Viscum album is listed in the Homeopathic Pharmacopoeia of the United States, which is the officially recognized compendium for homeopathic drugs in this country.[71] Although the U.S. Food and Drug Administration (FDA) has regulatory authority over homeopathic drugs, this authority is usually not exercised unless the drugs are formulated for injection, such as the mistletoe product described in this summary.

In this summary, the mistletoe extract or product used in each study will be specified wherever possible.

References

1. Jung ML, Baudino S, Ribéreau-Gayon G, et al.: Characterization of cytotoxic proteins from mistletoe (Viscum album L.). Cancer Lett 51 (2): 103-8, 1990. [PUBMED Abstract]
2. Kuttan G, Vasudevan DM, Kuttan R: Effect of a preparation from Viscum album on tumor development in vitro and in mice. J Ethnopharmacol 29 (1): 35-41, 1990. [PUBMED Abstract]
3. Walzel H, Jonas L, Rosin T, et al.: Relationship between internalization kinetics and cytotoxicity of mistletoe lectin I to L1210 leukaemia cells. Folia Biol (Praha) 36 (3-4): 181-8, 1990. [PUBMED Abstract]
4. Janssen O, Scheffler A, Kabelitz D: In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). Arzneimittelforschung 43 (11): 1221-7, 1993. [PUBMED Abstract]
5. Jurin M, Zarković N, Hrzenjak M, et al.: Antitumorous and immunomodulatory effects of the Viscum album L. preparation Isorel. Oncology 50 (6): 393-8, 1993 Nov-Dec. [PUBMED Abstract]
6. Schaller G, Urech K, Giannattasio M: Cytotoxicity of different viscotoxins and extracts from the European subspecies Viscum album L. Phytother Res 10 (6): 473-7, 1996.
7. Gabius HJ, Darro F, Remmelink M, et al.: Evidence for stimulation of tumor proliferation in cell lines and histotypic cultures by clinically relevant low doses of the galactoside-binding mistletoe lectin, a component of proprietary extracts. Cancer Invest 19 (2): 114-26, 2001. [PUBMED Abstract]
8. Maier G, Fiebig HH: Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Anticancer Drugs 13 (4): 373-9, 2002. [PUBMED Abstract]
9. Franz H: Mistletoe lectins and their A and B chains. Oncology 43 (Suppl 1): 23-34, 1986. [PUBMED Abstract]
10. Mengs U, Göthel D, Leng-Peschlow E: Mistletoe extracts standardized to mistletoe lectins in oncology: review on current status of preclinical research. Anticancer Res 22 (3): 1399-407, 2002 May-Jun. [PUBMED Abstract]
11. Podlech O, Harter PN, Mittelbronn M, et al.: Fermented mistletoe extract as a multimodal antitumoral agent in gliomas. Evid Based Complement Alternat Med 2012: 501796, 2012. [PUBMED Abstract]
12. Schötterl S, Hübner M, Armento A, et al.: Viscumins functionally modulate cell motility-associated gene expression. Int J Oncol 50 (2): 684-696, 2017. [PUBMED Abstract]
13. Hostanska K, Hajto T, Spagnoli GC, et al.: A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Nat Immun 14 (5-6): 295-304, 1995. [PUBMED Abstract]
14. Beuth J, Stoffel B, Ko HL, et al.: Immunomodulating ability of galactoside-specific lectin standardized and depleted mistletoe extract. Arzneimittelforschung 45 (11): 1240-2, 1995. [PUBMED Abstract]
15. Lenartz D, Stoffel B, Menzel J, et al.: Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients. Anticancer Res 16 (6B): 3799-802, 1996 Nov-Dec. [PUBMED Abstract]
16. Fischer S, Scheffler A, Kabelitz D: Oligoclonal in vitro response of CD4 T cells to vesicles of mistletoe extracts in mistletoe-treated cancer patients. Cancer Immunol Immunother 44 (3): 150-6, 1997. [PUBMED Abstract]
17. Preisfeld A: Influence of aqueous mistletoe preparations on humoral immune parameters with emphasis on the cytotoxicity of human complement in breast cancer patients. Forsch Komplementarmed 4 (4): 224-8, 1997.
18. Chernyshov VP, Omelchenko LI, Heusser P, et al.: Immunomodulatory actions of Viscum album (Iscador) in children with recurrent respiratory disease as a result of the Chernobyl nuclear accident. Complement Ther Med 5 (3): 141-6, 1997.
19. Heiny BM, Albrecht V, Beuth J: Correlation of immune cell activities and beta-endorphin release in breast carcinoma patients treated with galactose-specific lectin standardized mistletoe extract. Anticancer Res 18 (1B): 583-6, 1998 Jan-Feb. [PUBMED Abstract]
20. Stein GM, Schaller G, Pfüller U, et al.: Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat. Biochim Biophys Acta 1426 (1): 80-90, 1999. [PUBMED Abstract]
21. Stein GM, Schaller G, Pfüller U, et al.: Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes. Anticancer Res 19 (2A): 1037-42, 1999 Mar-Apr. [PUBMED Abstract]
22. Mistletoe. In: Murray MT: The Healing Power of Herbs. Prima Publishing, 1995, pp 253-9.
23. Lenartz D, Dott U, Menzel J, et al.: Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Res 20 (3B): 2073-6, 2000 May-Jun. [PUBMED Abstract]
24. 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 37 (1): 23-31, 2001. [PUBMED Abstract]
25. 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 168 (1): 72-5, 2002. [PUBMED Abstract]
26. Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
27. Saha C, Das M, Stephen-Victor E, et al.: Differential Effects of Viscum album Preparations on the Maturation and Activation of Human Dendritic Cells and CD4⁺ T Cell Responses. Molecules 21 (7): , 2016. [PUBMED Abstract]
28. Hegde P, Maddur MS, Friboulet A, et al.: Viscum album exerts anti-inflammatory effect by selectively inhibiting cytokine-induced expression of cyclooxygenase-2. PLoS One 6 (10): e26312, 2011. [PUBMED Abstract]
29. Elluru SR, VAN Huyen JP, Delignat S, et al.: Antiangiogenic properties of viscum album extracts are associated with endothelial cytotoxicity. Anticancer Res 29 (8): 2945-50, 2009. [PUBMED Abstract]
30. 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 8: 161, 2008. [PUBMED Abstract]
31. Elluru S, Duong Van Huyen JP, Delignat S, et al.: Molecular mechanisms underlying the immunomodulatory effects of mistletoe (Viscum album L.) extracts Iscador. Arzneimittelforschung 56 (6A): 461-6, 2006. [PUBMED Abstract]
32. Frohne D, Pfander HJ: Viscum album. In: Frohne D, Pfander HJ: Giftpflanzen: ein Handbuch für Apotheker, Ärzte, Toxikologen und Biologen. 3rd rev. ed. Wissenschaftliche Verlagsgesellschaft, 1987, pp 179-80.
33. Pusztai A, Grant G, Pfuller U, et al.: Nutritional and metabolic effects of mistletoe lectin ML-1 (type 2 RIP) in the rat. In: European Cooperation in the Field of Scientific and Technical Research: COST 98: Effects of Antinutrients on the Nutritional Value of Legume Diets. European Commission, Directorate-General XII, Science, Research and Development, 1998, pp 164-7.
34. Pusztai A, Grant G, Gelencsér E, et al.: Effects of an orally administered mistletoe (type-2 RIP) lectin on growth, body composition, small intestinal structure, and insulin levels in young rats. J Nutr Biochem 9 (1): 31-6, 1998.
35. Ewen SWB, Bardocz S, Grant G, et al.: The effects of PHA and mistletoe lectin binding to epithelium of rat and mouse gut. In: European Cooperation in the Field of Scientific and Technical Research: COST 98: Effects of Antinutrients on the Nutritional Value of Legume Diets. European Commission, Directorate-General XII, Science, Research and Development, 1998, pp 221-5.
36. Pryme IF, Bardocz S, Grant G, et al.: The plant lectins PHA and ML-1 suppress the growth of a lymphosarcoma tumour in mice. In: European Cooperation in the Field of Scientific and Technical Research: COST 98: Effects of Antinutrients on the Nutritional Value of Legume Diets. European Commission, Directorate-General XII, Science, Research and Development, 1998, pp 215-20.
37. Tubeuf KFv, Neckel G, Marzell H: Monographie der Mistel. R. Oldenbourg, 1923.
38. Teuscher E: Viscum album. In: Hansel R, Keller K, Rimpler H, et al.: Hagers Handbuch der Pharmazeutischen Praxis, Vol. 6. 5th ed. Springer-Verlag, 1994, pp 1160-83.
39. 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 7 (3): 57-66, 68-72, 74-6 passim, 2001 May-Jun. [PUBMED Abstract]
40. Capernaros Z: The golden bough: the case for mistletoe. Eur J Herbal Med 1 (1):19-24, 1994.
41. Schrader G, Apel K: Isolation and characterization of cDNAs encoding viscotoxins of mistletoe (Viscum album). Eur J Biochem 198 (3): 549-53, 1991. [PUBMED Abstract]
42. Gabius HJ, Gabius S, Joshi SS, et al.: From ill-defined extracts to the immunomodulatory lectin: will there be a reason for oncological application of mistletoe? Planta Med 60 (1): 2-7, 1994. [PUBMED Abstract]
43. Samtleben R, Hajto T, Hostanska K, et al.: Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic). In: Wagner H, ed.: Immunomodulatory Agents from Plants. Birkhauser Verlag, 1999, pp 223-41.
44. Abdullaev FI, de Mejia EG: Antitumor effect of plant lectins. Nat Toxins 5 (4): 157-63, 1997. [PUBMED Abstract]
45. Kilpatrick DC: Mechanisms and assessment of lectin-mediated mitogenesis. Mol Biotechnol 11 (1): 55-65, 1999. [PUBMED Abstract]
46. Horneber MA, Bueschel G, Huber R, et al.: Mistletoe therapy in oncology. Cochrane Database Syst Rev (2): CD003297, 2008. [PUBMED Abstract]
47. Khil LY, Kim W, Lyu S, et al.: Mechanisms involved in Korean mistletoe lectin-induced apoptosis of cancer cells. World J Gastroenterol 13 (20): 2811-8, 2007. [PUBMED Abstract]
48. Kim MS, Lee J, Lee KM, et al.: Involvement of hydrogen peroxide in mistletoe lectin-II-induced apoptosis of myeloleukemic U937 cells. Life Sci 73 (10): 1231-43, 2003. [PUBMED Abstract]
49. Choi SH, Lyu SY, Park WB: Mistletoe lectin induces apoptosis and telomerase inhibition in human A253 cancer cells through dephosphorylation of Akt. Arch Pharm Res 27 (1): 68-76, 2004. [PUBMED Abstract]
50. Romagnoli S, Fogolari F, Catalano M, et al.: NMR solution structure of viscotoxin C1 from Viscum album species Coloratum ohwi: toward a structure-function analysis of viscotoxins. Biochemistry 42 (43): 12503-10, 2003. [PUBMED Abstract]
51. Yoon TJ, Yoo YC, Kang TB, et al.: Antitumor activity of the Korean mistletoe lectin is attributed to activation of macrophages and NK cells. Arch Pharm Res 26 (10): 861-7, 2003. [PUBMED Abstract]
52. Ribéreau-Gayon G, Jung ML, Di Scala D, et al.: Comparison of the effects of fermented and unfermented mistletoe preparations on cultured tumor cells. Oncology 43 (Suppl 1): 35-41, 1986. [PUBMED Abstract]
53. Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995. [PUBMED Abstract]
54. Zee-Cheng RK: Anticancer research on Loranthaceae plants. Drugs Future 22 (5): 519-30, 1997.
55. Kaegi E: Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. CMAJ 158 (9): 1157-9, 1998. [PUBMED Abstract]
56. Stein G, Berg PA: Non-lectin component in a fermented extract from Viscum album L. grown on pines induces proliferation of lymphocytes from healthy and allergic individuals in vitro. Eur J Clin Pharmacol 47 (1): 33-8, 1994. [PUBMED Abstract]
57. Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994.
58. Wagner H, Jordan E, Feil B: Studies on the standardization of mistletoe preparations. Oncology 43 (Suppl 1): 16-22, 1986. [PUBMED Abstract]
59. Zarkovic N, Vukovic T, Loncaric I, et al.: An overview on anticancer activities of the Viscum album extract Isorel. Cancer Biother Radiopharm 16 (1): 55-62, 2001. [PUBMED Abstract]
60. Mellor D: Mistletoe in homoeopathic cancer treatment. Prof Nurse 4 (12): 605-7, 1989. [PUBMED Abstract]
61. Fellmer KE: A clinical trial of Iscador: follow-up treatment of irradiated genital carcinomata for the prevention of recurrences. Br Homeopath J 57: 43-7, 1968.
62. Kjaer M: Mistletoe (Iscador) therapy in stage IV renal adenocarcinoma. A phase II study in patients with measurable lung metastases. Acta Oncol 28 (4): 489-94, 1989. [PUBMED Abstract]
63. Schöffski P, Riggert S, Fumoleau P, et al.: Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group. Ann Oncol 15 (12): 1816-24, 2004. [PUBMED Abstract]
64. Matthes HF, Schad F, Buchwald D, et al.: Endoscopic ultrasound-guided fine-needle Injection of Viscum album L. (mistletoe; Helixor M) in the therapy of primary inoperable pancreas cancer: a pilot study. [Abstract] Gastroenterology 128 (Suppl 2): A-T988, A433-A434, 2005.
65. Matthes HF, Schad F, Schenk G: Viscum album in the therapy of primary inoperable hepatocellular carcinoma (HCC). [Abstract] Gastroenterology 126 (Suppl 2): A-755, A101-A102, 2004.
66. Schaefermeyer G, Schaefermeyer H: Treatment of pancreatic cancer with Viscum album (Iscador): a retrospective study of 292 patients 1986-1996. Complement Ther Med 6 (4): 172-7, 1998.
67. Kleeberg UR, Brocker EB, Lejeune F, et al.: Adjuvant trial in melanoma patients comparing rlFN-alpha to rlFN-gamma to Iscador to a control group after curative resection of high risk primary (>=3mm) or regional lymphnode metastasis (EORTC 18871). [Abstract] Eur J Cancer 35 (Suppl 4): A-264, s82, 1999.
68. Heiny BM, Albrecht V, Beuth J: Stabilization of quality of life with mistletoe lectin-1-standardized extract in advanced colorectal carcinoma. Onkologe 4 (Suppl 1): S35-9, 1998.
69. Wetzel D, Schäfer M: Results of a randomised placebo-controlled multicentre study with PS76A2 (standardised mistletoe preparation) in patients with breast cancer receiving adjuvant chemotherapy. [Abstract] Phytomedicine 7 (Suppl 2): A-SL-66, 2000.
70. Cho JS, Na KJ, Lee Y, et al.: Chemical Pleurodesis Using Mistletoe Extraction (ABNOVAviscum(®) Injection) for Malignant Pleural Effusion. Ann Thorac Cardiovasc Surg 22 (1): 20-6, 2016. [PUBMED Abstract]
71. Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States: Homoeopathic Pharmacopoeia of the United States. 2002, Monograph 9444 Visc.

Mistletoe has been used for centuries for its medicinal properties.[1-6] It was reportedly used by the Druids and the ancient Greeks, and it appears in legend and folklore as a panacea. It has been used in various forms to treat cancer, epilepsy, infertility, menopausal symptoms, nervous tension, asthma, hypertension, headache, and dermatitis. The use of mistletoe in the treatment of cancer is about 100 years old, and its use in the treatment of other indications is much older. Modern interest in mistletoe as an anticancer treatment began in the 1920s. Most of the results of clinical studies have been published exclusively in German. For more information, see the Human/Clinical Studies section.

Another reported activity of mistletoe that may be relevant to optimum functioning of the immune system in individuals with cancer is stabilization of the DNA in white blood cells, including white blood cells that have been exposed to DNA-damaging chemotherapy drugs.[7-11]

Mistletoe has been shown to stimulate increases in the number and the activity of various types of white blood cells.[2,3,9,11-53] Immune system–enhancing cytokines, such as interleukin-1, interleukin-6, and tumor necrosis factor-alpha, are released by white blood cells after exposure to mistletoe extracts.[1,3,7,9-11,14,19,29,33,37,42-46,48-50,52-54] Other evidence suggests that mistletoe exerts its cytotoxic effects by interfering with protein synthesis in target cells [3,4,8,11,33,42-46,52,55-63] and by inducing apoptosis.[3,11,36,42,46,52,64-66] Mistletoe may also serve a bridging function, bringing together immune system effector cells and tumor cells.[18,67]

References

1. Capernaros Z: The golden bough: the case for mistletoe. Eur J Herbal Med 1 (1):19-24, 1994.
2. Mistletoe. In: Murray MT: The Healing Power of Herbs. Prima Publishing, 1995, pp 253-9.
3. Samtleben R, Hajto T, Hostanska K, et al.: Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic). In: Wagner H, ed.: Immunomodulatory Agents from Plants. Birkhauser Verlag, 1999, pp 223-41.
4. Olsnes S, Stirpe F, Sandvig K, et al.: Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (mistletoe). J Biol Chem 257 (22): 13263-70, 1982. [PUBMED Abstract]
5. Becker H: Botany of European mistletoe (Viscum album L.). Oncology 43 (Suppl 1): 2-7, 1986. [PUBMED Abstract]
6. Watkins D: A berry Christmas. Nurs Times 93 (51): 28-9, 1997 Dec 17-23. [PUBMED Abstract]
7. Büssing A, Azhari T, Ostendorp H, et al.: Viscum album L. extracts reduce sister chromatid exchanges in cultured peripheral blood mononuclear cells. Eur J Cancer 30A (12): 1836-41, 1994. [PUBMED Abstract]
8. Büssing A, Lehnert A, Schink M, et al.: Effect of Viscum album L. on rapidly proliferating amniotic fluid cells. Sister chromatid exchange frequency and proliferation index. Arzneimittelforschung 45 (1): 81-3, 1995. [PUBMED Abstract]
9. Büssing A, Regnery A, Schweizer K: Effects of Viscum album L. on cyclophosphamide-treated peripheral blood mononuclear cells in vitro: sister chromatid exchanges and activation/proliferation marker expression. Cancer Lett 94 (2): 199-205, 1995. [PUBMED Abstract]
10. Bussing A, Jungmann H, Suzart K, et al.: Suppression of sister chromatid exchange-inducing DNA lesions in cultured peripheral blood mononuclear cells by Viscum album L. J Exp Clin Cancer Res 15 (2): 107-14, 1996.
11. Büssing A, Suzart K, Bergmann J, et al.: Induction of apoptosis in human lymphocytes treated with Viscum album L. is mediated by the mistletoe lectins. Cancer Lett 99 (1): 59-72, 1996. [PUBMED Abstract]
12. 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 (1): 43-8, 1981. [PUBMED Abstract]
13. Bloksma N, Schmiermann P, de Reuver M, et al.: Stimulation of humoral and cellular immunity by Viscum preparations. Planta Med 46 (4): 221-7, 1982. [PUBMED Abstract]
14. Hajto T: Immunomodulatory effects of iscador: a Viscum album preparation. Oncology 43 (Suppl 1): 51-65, 1986. [PUBMED Abstract]
15. Hajto T, Lanzrein C: Natural killer and antibody-dependent cell-mediated cytotoxicity activities and large granular lymphocyte frequencies in Viscum album-treated breast cancer patients. Oncology 43 (2): 93-7, 1986. [PUBMED Abstract]
16. Hamprecht K, Handgretinger R, Voetsch W, et al.: Mediation of human NK-activity by components in extracts of Viscum album. Int J Immunopharmacol 9 (2): 199-209, 1987. [PUBMED Abstract]
17. Hajto T, Hostanska K, Gabius HJ: Modulatory potency of the beta-galactoside-specific lectin from mistletoe extract (Iscador) on the host defense system in vivo in rabbits and patients. Cancer Res 49 (17): 4803-8, 1989. [PUBMED Abstract]
18. Mueller EA, Hamprecht K, Anderer FA: Biochemical characterization of a component in extracts of Viscum album enhancing human NK cytotoxicity. Immunopharmacology 17 (1): 11-8, 1989 Jan-Feb. [PUBMED Abstract]
19. Hajto T, Hostanska K, Frei K, et al.: Increased secretion of tumor necrosis factors alpha, interleukin 1, and interleukin 6 by human mononuclear cells exposed to beta-galactoside-specific lectin from clinically applied mistletoe extract. Cancer Res 50 (11): 3322-6, 1990. [PUBMED Abstract]
20. Beuth J, Ko HL, Gabius HJ, et al.: Behavior of lymphocyte subsets and expression of activation markers in response to immunotherapy with galactoside-specific lectin from mistletoe in breast cancer patients. Clin Investig 70 (8): 658-61, 1992. [PUBMED Abstract]
21. Kuttan G, Kuttan R: Immunological mechanism of action of the tumor reducing peptide from mistletoe extract (NSC 635089) cellular proliferation. Cancer Lett 66 (2): 123-30, 1992. [PUBMED Abstract]
22. Kuttan G, Kuttan R: Immunomodulatory activity of a peptide isolated from Viscum album extract (NSC 635 089). Immunol Invest 21 (4): 285-96, 1992. [PUBMED Abstract]
23. Gabius HJ, Walzel H, Joshi SS, et al.: The immunomodulatory beta-galactoside-specific lectin from mistletoe: partial sequence analysis, cell and tissue binding, and impact on intracellular biosignalling of monocytic leukemia cells. Anticancer Res 12 (3): 669-75, 1992 May-Jun. [PUBMED Abstract]
24. Beuth J, Ko HL, Tunggal L, et al.: Thymocyte proliferation and maturation in response to galactoside-specific mistletoe lectin-1. In Vivo 7 (5): 407-10, 1993 Sep-Oct. [PUBMED Abstract]
25. Timoshenko AV, Gabius HJ: Efficient induction of superoxide release from human neutrophils by the galactoside-specific lectin from Viscum album. Biol Chem Hoppe Seyler 374 (4): 237-43, 1993. [PUBMED Abstract]
26. Timoshenko AV, Kayser K, Drings P, et al.: Modulation of lectin-triggered superoxide release from neutrophils of tumor patients with and without chemotherapy. Anticancer Res 13 (5C): 1789-92, 1993 Sep-Oct. [PUBMED Abstract]
27. Kuttan G: Tumoricidal activity of mouse peritoneal macrophages treated with Viscum album extract. Immunol Invest 22 (6-7): 431-40, 1993 Aug-Oct. [PUBMED Abstract]
28. Beuth J, Ko HL, Tunggal L, et al.: Immunoprotective activity of the galactoside-specific mistletoe lectin in cortisone-treated BALB/c-mice. In Vivo 8 (6): 989-92, 1994 Nov-Dec. [PUBMED Abstract]
29. Heiny BM, Beuth J: Mistletoe extract standardized for the galactoside-specific lectin (ML-1) induces beta-endorphin release and immunopotentiation in breast cancer patients. Anticancer Res 14 (3B): 1339-42, 1994 May-Jun. [PUBMED Abstract]
30. Stein G, Berg PA: Non-lectin component in a fermented extract from Viscum album L. grown on pines induces proliferation of lymphocytes from healthy and allergic individuals in vitro. Eur J Clin Pharmacol 47 (1): 33-8, 1994. [PUBMED Abstract]
31. Timoshenko AV, Gabius HJ: Influence of the galactoside-specific lectin from Viscum album and its subunits on cell aggregation and selected intracellular parameters of rat thymocytes. Planta Med 61 (2): 130-3, 1995. [PUBMED Abstract]
32. Timoshenko AV, Cherenkevich SN, Gabius HJ: Viscum album agglutinin-induced aggregation of blood cells and the lectin effects on neutrophil function. Biomed Pharmacother 49 (3): 153-8, 1995. [PUBMED Abstract]
33. Hostanska K, Hajto T, Spagnoli GC, et al.: A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Nat Immun 14 (5-6): 295-304, 1995. [PUBMED Abstract]
34. Beuth J, Stoffel B, Ko HL, et al.: Immunomodulating ability of galactoside-specific lectin standardized and depleted mistletoe extract. Arzneimittelforschung 45 (11): 1240-2, 1995. [PUBMED Abstract]
35. Lenartz D, Stoffel B, Menzel J, et al.: Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients. Anticancer Res 16 (6B): 3799-802, 1996 Nov-Dec. [PUBMED Abstract]
36. Fischer S, Scheffler A, Kabelitz D: Oligoclonal in vitro response of CD4 T cells to vesicles of mistletoe extracts in mistletoe-treated cancer patients. Cancer Immunol Immunother 44 (3): 150-6, 1997. [PUBMED Abstract]
37. Preisfeld A: Influence of aqueous mistletoe preparations on humoral immune parameters with emphasis on the cytotoxicity of human complement in breast cancer patients. Forsch Komplementarmed 4 (4): 224-8, 1997.
38. Chernyshov VP, Omelchenko LI, Heusser P, et al.: Immunomodulatory actions of Viscum album (Iscador) in children with recurrent respiratory disease as a result of the Chernobyl nuclear accident. Complement Ther Med 5 (3): 141-6, 1997.
39. Heiny BM, Albrecht V, Beuth J: Correlation of immune cell activities and beta-endorphin release in breast carcinoma patients treated with galactose-specific lectin standardized mistletoe extract. Anticancer Res 18 (1B): 583-6, 1998 Jan-Feb. [PUBMED Abstract]
40. Stein GM, Schaller G, Pfüller U, et al.: Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat. Biochim Biophys Acta 1426 (1): 80-90, 1999. [PUBMED Abstract]
41. Stein GM, Schaller G, Pfüller U, et al.: Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes. Anticancer Res 19 (2A): 1037-42, 1999 Mar-Apr. [PUBMED Abstract]
42. Mengs U, Göthel D, Leng-Peschlow E: Mistletoe extracts standardized to mistletoe lectins in oncology: review on current status of preclinical research. Anticancer Res 22 (3): 1399-407, 2002 May-Jun. [PUBMED Abstract]
43. Bocci V: Mistletoe (viscum album) lectins as cytokine inducers and immunoadjuvant in tumor therapy. A review. J Biol Regul Homeost Agents 7 (1): 1-6, 1993 Jan-Mar. [PUBMED Abstract]
44. Gabius HJ, Gabius S, Joshi SS, et al.: From ill-defined extracts to the immunomodulatory lectin: will there be a reason for oncological application of mistletoe? Planta Med 60 (1): 2-7, 1994. [PUBMED Abstract]
45. Zee-Cheng RK: Anticancer research on Loranthaceae plants. Drugs Future 22 (5): 519-30, 1997.
46. Kaegi E: Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. CMAJ 158 (9): 1157-9, 1998. [PUBMED Abstract]
47. Lenartz D, Dott U, Menzel J, et al.: Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Res 20 (3B): 2073-6, 2000 May-Jun. [PUBMED Abstract]
48. 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 168 (1): 72-5, 2002. [PUBMED Abstract]
49. Schaefermeyer G, Schaefermeyer H: Treatment of pancreatic cancer with Viscum album (Iscador): a retrospective study of 292 patients 1986-1996. Complement Ther Med 6 (4): 172-7, 1998.
50. Kunze E, Schulz H, Gabius HJ: Inability of galactoside-specific mistletoe lectin to inhibit N-methyl-N-nitrosourea-induced tumor development in the urinary bladder of rats and to mediate a local cellular immune response after long-term administration. J Cancer Res Clin Oncol 124 (2): 73-87, 1998. [PUBMED Abstract]
51. Kunze E, Schulz H, Adamek M, et al.: Long-term administration of galactoside-specific mistletoe lectin in an animal model: no protection against N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder carcinogenesis in rats and no induction of a relevant local cellular immune response. J Cancer Res Clin Oncol 126 (3): 125-38, 2000. [PUBMED Abstract]
52. Mengs U, Schwarz T, Bulitta M, et al.: Antitumoral effects of an intravesically applied aqueous mistletoe extract on urinary bladder carcinoma MB49 in mice. Anticancer Res 20 (5B): 3565-8, 2000 Sep- Oct. [PUBMED Abstract]
53. Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
54. Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994.
55. Stirpe F, Sandvig K, Olsnes S, et al.: Action of viscumin, a toxic lectin from mistletoe, on cells in culture. J Biol Chem 257 (22): 13271-7, 1982. [PUBMED Abstract]
56. Walzel H, Jonas L, Rosin T, et al.: Relationship between internalization kinetics and cytotoxicity of mistletoe lectin I to L1210 leukaemia cells. Folia Biol (Praha) 36 (3-4): 181-8, 1990. [PUBMED Abstract]
57. Franz H: Mistletoe lectins and their A and B chains. Oncology 43 (Suppl 1): 23-34, 1986. [PUBMED Abstract]
58. Sweeney EC, Palmer RA, Pfüller U: Crystallization of the ribosome inactivating protein ML1 from Viscum album (mistletoe) complexed with beta-D-galactose. J Mol Biol 234 (4): 1279-81, 1993. [PUBMED Abstract]
59. Jung ML, Baudino S, Ribéreau-Gayon G, et al.: Characterization of cytotoxic proteins from mistletoe (Viscum album L.). Cancer Lett 51 (2): 103-8, 1990. [PUBMED Abstract]
60. Gabius HJ, Darro F, Remmelink M, et al.: Evidence for stimulation of tumor proliferation in cell lines and histotypic cultures by clinically relevant low doses of the galactoside-binding mistletoe lectin, a component of proprietary extracts. Cancer Invest 19 (2): 114-26, 2001. [PUBMED Abstract]
61. Dietrich JB, Ribéreau-Gayon G, Jung ML, et al.: Identity of the N-terminal sequences of the three A chains of mistletoe (Viscum album L.) lectins: homology with ricin-like plant toxins and single-chain ribosome-inhibiting proteins. Anticancer Drugs 3 (5): 507-11, 1992. [PUBMED Abstract]
62. Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995. [PUBMED Abstract]
63. Burger AM, Mengs U, Schüler JB, et al.: Anticancer activity of an aqueous mistletoe extract (AME) in syngeneic murine tumor models. Anticancer Res 21 (3B): 1965-8, 2001 May-Jun. [PUBMED Abstract]
64. Janssen O, Scheffler A, Kabelitz D: In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). Arzneimittelforschung 43 (11): 1221-7, 1993. [PUBMED Abstract]
65. Zarkovic N, Vukovic T, Loncaric I, et al.: An overview on anticancer activities of the Viscum album extract Isorel. Cancer Biother Radiopharm 16 (1): 55-62, 2001. [PUBMED Abstract]
66. Maier G, Fiebig HH: Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Anticancer Drugs 13 (4): 373-9, 2002. [PUBMED Abstract]
67. Mueller EA, Anderer FA: Chemical specificity of effector cell/tumor cell bridging by a Viscum album rhamnogalacturonan enhancing cytotoxicity of human NK cells. Immunopharmacology 19 (1): 69-77, 1990 Jan-Feb. [PUBMED Abstract]

The immune system–stimulating and cytotoxic properties of mistletoe have been investigated in laboratory and animal studies.

Viscotoxins and lectins have been investigated as active components in mistletoe; most research has focused on the lectins.[1-9] Purified mistletoe lectins have demonstrated cytotoxic and immune system–stimulating activities. Four different lectins have been identified in mistletoe extracts as follows:

ML-1 (or viscumin) may be responsible for many of mistletoe’s biological effects. When a laboratory method was used to selectively deplete ML-1 from Viscum album extracts, their cytotoxic and immune system–stimulating properties were markedly reduced.[10,11] It should be noted that fermentation eliminates most of the ML-1 in mistletoe extracts. Iscador, and other fermented mistletoe extracts, contain only the mistletoe lectins ML-2 and ML-3, whereas the proteins of the ML-1 complex are missing.[12-14] Polysaccharide and oligosaccharide components of mistletoe extracts with substantial immune-stimulating properties have been reviewed.[15,16]

The molecular structure of ML-1 consists of an alpha chain and a beta chain, which can be separated from one another.[1,6-9,13,17,18] Each chain type appears to mediate a subset of the activities described for the intact lectin. Cytotoxicity is associated mainly with the alpha chain. In laboratory studies, the ML-1 alpha chain has been coupled to monoclonal antibodies to produce immunotoxins that target and kill specific cell types.[19-21]

Recombinant ML-1, rML (also known as rViscumin or aviscumine) appears to have the same efficacy as plant-based ML-1 in laboratory studies.[22] Because this is not an extract of mistletoe, it is out of the purview of this summary.

The beta chain of ML-1 is responsible for binding to the surface of a target cell.[23] Studies of mistletoe lectin binding to cancer cells have examined whether the extent of cell binding can predict disease outcome or survival. Studies show that the prognostic value of ML-1 binding depends on the type of cancer.[24] For human breast cancer cells, the amount of lectin-bound cells correlates positively with disease outcome. However, for human adenocarcinoma of the lung, there is no correlation between the amount of lectin-bound cells and disease survival.[25] Though much research has looked at this particular aspect, there have not been studies that directly link the concentration of that component to any clinical activity of mistletoe.

Laboratory studies have shown that mistletoe extracts can stimulate the activity of white blood cells in vitro and cause them to release molecules thought to be important for anticancer immune responses.[4,6,8,9,17,26-33] In addition, mistletoe extracts have demonstrated cytotoxic activity against a variety of mouse, rat, and human cancer cells in vitro.[1,8,23,34-37]

There are conflicting reports concerning the stimulation of cancer cell growth in vitro. In one study, the in vitro growth of several types of human cancer cells was stimulated by treatment with low doses of the purified lectin ML-1.[1] However, various other studies found that ML-1 and mistletoe extracts did not induce cell proliferation.[38,39]

Preclinical studies demonstrating biological effects on cancer cell lines and animal models are summarized in Table 1 and Table 2.

Studies of the ability of mistletoe to inhibit cancer cell growth in animals have yielded mixed and inconsistent results.[5-9,36,42-50] In most of these studies, mistletoe extracts were administered either by subcutaneous injection or by intraperitoneal injection; some of the differences in results may have resulted from the difference in route of administration. For example, IscadorM administration was associated with a prolonged survival of female Swiss mice when the route of administration was intraperitoneal [51] but not when the route was subcutaneous.[52] Other differences between these two studies were the number of cells used in the Ehrlich ascites inoculum and the doses of IscadorM administered.

References

1. Gabius HJ, Darro F, Remmelink M, et al.: Evidence for stimulation of tumor proliferation in cell lines and histotypic cultures by clinically relevant low doses of the galactoside-binding mistletoe lectin, a component of proprietary extracts. Cancer Invest 19 (2): 114-26, 2001. [PUBMED Abstract]
2. Lenartz D, Dott U, Menzel J, et al.: Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Res 20 (3B): 2073-6, 2000 May-Jun. [PUBMED Abstract]
3. 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 37 (1): 23-31, 2001. [PUBMED Abstract]
4. 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 168 (1): 72-5, 2002. [PUBMED Abstract]
5. Kunze E, Schulz H, Adamek M, et al.: Long-term administration of galactoside-specific mistletoe lectin in an animal model: no protection against N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder carcinogenesis in rats and no induction of a relevant local cellular immune response. J Cancer Res Clin Oncol 126 (3): 125-38, 2000. [PUBMED Abstract]
6. Mengs U, Schwarz T, Bulitta M, et al.: Antitumoral effects of an intravesically applied aqueous mistletoe extract on urinary bladder carcinoma MB49 in mice. Anticancer Res 20 (5B): 3565-8, 2000 Sep- Oct. [PUBMED Abstract]
7. Burger AM, Mengs U, Schüler JB, et al.: Anticancer activity of an aqueous mistletoe extract (AME) in syngeneic murine tumor models. Anticancer Res 21 (3B): 1965-8, 2001 May-Jun. [PUBMED Abstract]
8. Mengs U, Göthel D, Leng-Peschlow E: Mistletoe extracts standardized to mistletoe lectins in oncology: review on current status of preclinical research. Anticancer Res 22 (3): 1399-407, 2002 May-Jun. [PUBMED Abstract]
9. Samtleben R, Hajto T, Hostanska K, et al.: Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic). In: Wagner H, ed.: Immunomodulatory Agents from Plants. Birkhauser Verlag, 1999, pp 223-41.
10. Janssen O, Scheffler A, Kabelitz D: In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). Arzneimittelforschung 43 (11): 1221-7, 1993. [PUBMED Abstract]
11. Beuth J, Stoffel B, Ko HL, et al.: Immunomodulating ability of galactoside-specific lectin standardized and depleted mistletoe extract. Arzneimittelforschung 45 (11): 1240-2, 1995. [PUBMED Abstract]
12. Wagner H, Jordan E, Feil B: Studies on the standardization of mistletoe preparations. Oncology 43 (Suppl 1): 16-22, 1986. [PUBMED Abstract]
13. Mistletoe. In: Murray MT: The Healing Power of Herbs. Prima Publishing, 1995, pp 253-9.
14. Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995. [PUBMED Abstract]
15. Stein GM, Büssing A, Schietzel M: Stimulation of the maturation of dendritic cells in vitro by a fermented mistletoe extract. Anticancer Res 22 (6C): 4215-9, 2002 Nov-Dec. [PUBMED Abstract]
16. Lyu SY, Kwon YJ, Joo HJ, et al.: Preparation of alginate/chitosan microcapsules and enteric coated granules of mistletoe lectin. Arch Pharm Res 27 (1): 118-26, 2004. [PUBMED Abstract]
17. Timoshenko AV, Gabius HJ: Efficient induction of superoxide release from human neutrophils by the galactoside-specific lectin from Viscum album. Biol Chem Hoppe Seyler 374 (4): 237-43, 1993. [PUBMED Abstract]
18. Dietrich JB, Ribéreau-Gayon G, Jung ML, et al.: Identity of the N-terminal sequences of the three A chains of mistletoe (Viscum album L.) lectins: homology with ricin-like plant toxins and single-chain ribosome-inhibiting proteins. Anticancer Drugs 3 (5): 507-11, 1992. [PUBMED Abstract]
19. Wiedłocha A, Sandvig K, Walzel H, et al.: Internalization and action of an immunotoxin containing mistletoe lectin A-chain. Cancer Res 51 (3): 916-20, 1991. [PUBMED Abstract]
20. Tonevitsky AG, Toptygin AYu, Pfuller U, et al.: Immunotoxin with mistletoe lectin I A-chain and ricin A-chain directed against CD5 antigen of human T-lymphocytes; comparison of efficiency and specificity. Int J Immunopharmacol 13 (7): 1037-41, 1991. [PUBMED Abstract]
21. Bocci V: Mistletoe (viscum album) lectins as cytokine inducers and immunoadjuvant in tumor therapy. A review. J Biol Regul Homeost Agents 7 (1): 1-6, 1993 Jan-Mar. [PUBMED Abstract]
22. Habeck M: Mistletoe compound enters clinical trials. Drug Discov Today 8 (2): 52-3, 2003. [PUBMED Abstract]
23. Müthing J, Meisen I, Kniep B, et al.: Tumor-associated CD75s gangliosides and CD75s-bearing glycoproteins with Neu5Acalpha2-6Galbeta1-4GlcNAc-residues are receptors for the anticancer drug rViscumin. FASEB J 19 (1): 103-5, 2005. [PUBMED Abstract]
24. Fritz P, Dippon J, Kierschke T, et al.: Impact of mistletoe lectin binding in breast cancer. Anticancer Res 24 (2C): 1187-92, 2004 Mar-Apr. [PUBMED Abstract]
25. Blonski K, Schumacher U, Burkholder I, et al.: Binding of recombinant mistletoe lectin (aviscumine) to resected human adenocarcinoma of the lung. Anticancer Res 25 (5): 3303-7, 2005 Sep-Oct. [PUBMED Abstract]
26. Timoshenko AV, Kayser K, Drings P, et al.: Modulation of lectin-triggered superoxide release from neutrophils of tumor patients with and without chemotherapy. Anticancer Res 13 (5C): 1789-92, 1993 Sep-Oct. [PUBMED Abstract]
27. Timoshenko AV, Gabius HJ: Influence of the galactoside-specific lectin from Viscum album and its subunits on cell aggregation and selected intracellular parameters of rat thymocytes. Planta Med 61 (2): 130-3, 1995. [PUBMED Abstract]
28. Timoshenko AV, Cherenkevich SN, Gabius HJ: Viscum album agglutinin-induced aggregation of blood cells and the lectin effects on neutrophil function. Biomed Pharmacother 49 (3): 153-8, 1995. [PUBMED Abstract]
29. Hostanska K, Hajto T, Spagnoli GC, et al.: A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Nat Immun 14 (5-6): 295-304, 1995. [PUBMED Abstract]
30. Fischer S, Scheffler A, Kabelitz D: Oligoclonal in vitro response of CD4 T cells to vesicles of mistletoe extracts in mistletoe-treated cancer patients. Cancer Immunol Immunother 44 (3): 150-6, 1997. [PUBMED Abstract]
31. Stein GM, Schaller G, Pfüller U, et al.: Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat. Biochim Biophys Acta 1426 (1): 80-90, 1999. [PUBMED Abstract]
32. Stein GM, Schaller G, Pfüller U, et al.: Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes. Anticancer Res 19 (2A): 1037-42, 1999 Mar-Apr. [PUBMED Abstract]
33. Hallek M: Interleukin-6-mediated cell growth in multiple myeloma--a role for Viscum album extracts? Onkologie 28 (8-9): 387, 2005. [PUBMED Abstract]
34. Schaller G, Urech K, Giannattasio M: Cytotoxicity of different viscotoxins and extracts from the European subspecies Viscum album L. Phytother Res 10 (6): 473-7, 1996.
35. Maier G, Fiebig HH: Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Anticancer Drugs 13 (4): 373-9, 2002. [PUBMED Abstract]
36. Zarkovic N, Vukovic T, Loncaric I, et al.: An overview on anticancer activities of the Viscum album extract Isorel. Cancer Biother Radiopharm 16 (1): 55-62, 2001. [PUBMED Abstract]
37. Zuzak TJ, Rist L, Eggenschwiler J, et al.: Paediatric medulloblastoma cells are susceptible to Viscum album (Mistletoe) preparations. Anticancer Res 26 (5A): 3485-92, 2006 Sep-Oct. [PUBMED Abstract]
38. Kelter G, Fiebig HH: Absence of tumor growth stimulation in a panel of 26 human tumor cell lines by mistletoe (Viscum album L.) extracts Iscador in vitro. Arzneimittelforschung 56 (6A): 435-40, 2006. [PUBMED Abstract]
39. Kelter G, Schierholz JM, Fischer IU, et al.: Cytotoxic activity and absence of tumor growth stimulation of standardized mistletoe extracts in human tumor models in vitro. Anticancer Res 27 (1A): 223-33, 2007 Jan-Feb. [PUBMED Abstract]
40. 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 14: 6, 2014. [PUBMED Abstract]
41. Podlech O, Harter PN, Mittelbronn M, et al.: Fermented mistletoe extract as a multimodal antitumoral agent in gliomas. Evid Based Complement Alternat Med 2012: 501796, 2012. [PUBMED Abstract]
42. Cebović T, Spasić S, Popović M: Cytotoxic effects of the Viscum album L. extract on Ehrlich tumour cells in vivo. Phytother Res 22 (8): 1097-103, 2008. [PUBMED Abstract]
43. Seifert G, Jesse P, Laengler A, et al.: Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro. Cancer Lett 264 (2): 218-28, 2008. [PUBMED Abstract]
44. Thies A, Dautel P, Meyer A, et al.: Low-dose mistletoe lectin-I reduces melanoma growth and spread in a scid mouse xenograft model. Br J Cancer 98 (1): 106-12, 2008. [PUBMED Abstract]
45. Van Huyen JP, Delignat S, Bayry J, et al.: Interleukin-12 is associated with the in vivo anti-tumor effect of mistletoe extracts in B16 mouse melanoma. Cancer Lett 243 (1): 32-7, 2006. [PUBMED Abstract]
46. 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 26 (6B): 4451-6, 2006 Nov-Dec. [PUBMED Abstract]
47. Braun JM, Ko HL, Schierholz JM, et al.: Standardized mistletoe extract augments immune response and down-regulates local and metastatic tumor growth in murine models. Anticancer Res 22 (6C): 4187-90, 2002 Nov-Dec. [PUBMED Abstract]
48. Pryme IF, Bardocz S, Pusztai A, et al.: Dietary mistletoe lectin supplementation and reduced growth of a murine non-Hodgkin lymphoma. Histol Histopathol 17 (1): 261-71, 2002. [PUBMED Abstract]
49. Elsässer-Beile U, Ruhnau T, Freudenberg N, et al.: Antitumoral effect of recombinant mistletoe lectin on chemically induced urinary bladder carcinogenesis in a rat model. Cancer 91 (5): 998-1004, 2001. [PUBMED Abstract]
50. Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
51. Khwaja TA, Dias CB, Pentecost S: Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids. Oncology 43 (Suppl 1): 42-50, 1986. [PUBMED Abstract]
52. Berger M, Schmähl D: Studies on the tumor-inhibiting efficacy of Iscador in experimental animal tumors. J Cancer Res Clin Oncol 105 (3): 262-5, 1983. [PUBMED Abstract]
53. Rostock M, Huber R, Greiner T, et al.: Anticancer activity of a lectin-rich mistletoe extract injected intratumorally into human pancreatic cancer xenografts. Anticancer Res 25 (3B): 1969-75, 2005 May-Jun. [PUBMED Abstract]
54. Jurin M, Zarković N, Hrzenjak M, et al.: Antitumorous and immunomodulatory effects of the Viscum album L. preparation Isorel. Oncology 50 (6): 393-8, 1993 Nov-Dec. [PUBMED Abstract]

Mistletoe has been evaluated as a treatment for people with cancer in numerous clinical studies.[1-20]

The mistletoe extracts and products studied in clinical trials were Iscador, Eurixor, Helixor, Lektinol, Isorel, abnobaVISCUM,[21] and recombinant lectin ML-1. For more information, see the appropriate subsections and tables in this section.

The findings from more than 50 clinical trials of mistletoe extracts in patients with cancer have been published, and several systematic reviews and meta-analyses of the results of these studies have been performed. Three of the most recent systematic reviews addressed quality of life (QOL), survival, and symptom relief in patients with various cancer types.[18,20,22] Most studies reported an improvement in QOL, as did a noncontrolled, nonrandomized, real-world study that analyzed patient registry data.[23]

In one systematic review that examined 26 randomized controlled trials (RCTs), 22 trials reported an improvement in QOL. All 10 of the nonRCTs also reported the same benefit. Improvement in fatigue, nausea and vomiting, depression, emotional well-being, and concentration were reported. Some of the studies were well designed, while others reported weaknesses.[22]

Tumor response, QOL, and psychological distress were measured in a review of 21 RCTs of various cancers in which different mistletoe preparations were used either alone, with chemotherapy, or with radiation therapy.[18] Survival times were included in 13 of the studies. Most of the studies reported benefits for patients, although this review was limited by small sample size and methodological weaknesses. Thus, the authors were unable to suggest practice guidelines for the use of mistletoe.

The oldest of these three reviews investigated the results of 10 RCTs that used a variety of mistletoe extracts in patients with various malignancies. There was no difference in survival or other benefits for cancer patients who received mistletoe. Therefore, mistletoe was not recommended as a curative or supportive care therapy.[20]

A systematic review of all controlled clinical studies of mistletoe found consistent improvement in chemotherapy-associated fatigue as well as other QOL measures.[22]

Although mistletoe was found to be therapeutically effective in most of the reported studies, many of the studies had one or more major design weaknesses as mentioned above that raised doubts about the reliability of the findings. These weaknesses include the following:

In addition, evaluation of the studies is often hindered by incomplete descriptions of the study design and by incomplete reporting of clinical data, including data about previous and concurrent therapies received by the patients. Note: In studies with small numbers of patients, the mean survival time can be greatly exaggerated if one or more patients exhibit unusually long survival; median survival, therefore, is a less biased measure.

A selection of studies is discussed below, organized by the type of mistletoe extract used. Studies on Iscador are summarized in Table 3. Studies on Helixor, abnobaVISCUM, Eurixor, Isorel, and Lektinol are summarized in Table 4. Eurixor, Isorel, and Vysorel are no longer available on the market for sale.

References

1. Lenartz D, Dott U, Menzel J, et al.: Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Res 20 (3B): 2073-6, 2000 May-Jun. [PUBMED Abstract]
2. 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 37 (1): 23-31, 2001. [PUBMED Abstract]
3. 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 168 (1): 72-5, 2002. [PUBMED Abstract]
4. 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 7 (3): 57-66, 68-72, 74-6 passim, 2001 May-Jun. [PUBMED Abstract]
5. Kleeberg UR, Suciu S, Bröcker 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 40 (3): 390-402, 2004. [PUBMED Abstract]
6. Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States: Homoeopathic Pharmacopoeia of the United States. 2002, Monograph 9444 Visc.
7. Tröger W, Jezdić S, Ždrale Z, et al.: Quality of life and neutropenia in patients with early stage breast cancer: a randomized pilot study comparing additional treatment with mistletoe extract to chemotherapy alone . Breast Cancer: Basic and Clinical Research 3: 35-45, 2009.
8. Grossarth-Maticek R, Ziegler R: Prospective controlled cohort studies on long-term therapy of breast cancer patients with a mistletoe preparation (Iscador). Forsch Komplementmed 13 (5): 285-92, 2006. [PUBMED Abstract]
9. Grossarth-Maticek R, Ziegler R: Prospective controlled cohort studies on long-term therapy of cervical cancer patients with a mistletoe preparation (Iscador). Forsch Komplementmed 14 (3): 140-7, 2007. [PUBMED Abstract]
10. Grossarth-Maticek R, Ziegler R: Randomized and non-randomized prospective controlled cohort studies in matched pair design for the long-term therapy of corpus uteri cancer patients with a mistletoe preparation (Iscador). Eur J Med Res 13 (3): 107-20, 2008. [PUBMED Abstract]
11. Grossarth-Maticek R, Ziegler R: Prospective controlled cohort studies on long-term therapy of ovairian cancer patients with mistletoe (Viscum album L.) extracts iscador. Arzneimittelforschung 57 (10): 665-78, 2007. [PUBMED Abstract]
12. Bar-Sela G, Goldberg H, Beck D, et al.: Reducing malignant ascites accumulation by repeated intraperitoneal administrations of a Viscum album extract. Anticancer Res 26 (1B): 709-13, 2006 Jan-Feb. [PUBMED Abstract]
13. Wetzel D, Schäfer M: Results of a randomised placebo-controlled multicentre study with PS76A2 (standardised mistletoe preparation) in patients with breast cancer receiving adjuvant chemotherapy. [Abstract] Phytomedicine 7 (Suppl 2): A-SL-66, 2000.
14. Schöffski P, Riggert S, Fumoleau P, et al.: Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group. Ann Oncol 15 (12): 1816-24, 2004. [PUBMED Abstract]
15. Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
16. Kienle GS, Berrino F, Büssing A, et al.: Mistletoe in cancer - a systematic review on controlled clinical trials. Eur J Med Res 8 (3): 109-19, 2003. [PUBMED Abstract]
17. Kienle GS, Glockmann A, Schink M, et al.: Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research. J Exp Clin Cancer Res 28: 79, 2009. [PUBMED Abstract]
18. Horneber MA, Bueschel G, Huber R, et al.: Mistletoe therapy in oncology. Cochrane Database Syst Rev (2): CD003297, 2008. [PUBMED Abstract]
19. Kienle GS, Kiene H: Complementary cancer therapy: a systematic review of prospective clinical trials on anthroposophic mistletoe extracts. Eur J Med Res 12 (3): 103-19, 2007. [PUBMED Abstract]
20. Ernst E, Schmidt K, Steuer-Vogt MK: Mistletoe for cancer? A systematic review of randomised clinical trials. Int J Cancer 107 (2): 262-7, 2003. [PUBMED Abstract]
21. Mabed M, El-Helw L, Shamaa S: Phase II study of viscum fraxini-2 in patients with advanced hepatocellular carcinoma. Br J Cancer 90 (1): 65-9, 2004. [PUBMED Abstract]
22. Kienle GS, Kiene H: Review article: Influence of Viscum album L (European mistletoe) extracts on quality of life in cancer patients: a systematic review of controlled clinical studies. Integr Cancer Ther 9 (2): 142-57, 2010. [PUBMED Abstract]
23. Oei SL, Thronicke A, Kröz M, et al.: Impact of Oncological Therapy and Viscum album L Treatment on Cancer-Related Fatigue and Internal Coherence in Nonmetastasized Breast Cancer Patients. Integr Cancer Ther 19: 1534735420917211, 2020 Jan-Dec. [PUBMED Abstract]
24. Büssing A, Raak C, Ostermann T: Quality of life and related dimensions in cancer patients treated with mistletoe extract (iscador): a meta-analysis. Evid Based Complement Alternat Med 2012: 219402, 2012. [PUBMED Abstract]
25. 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 49 (5): 1058-64, 2013. [PUBMED Abstract]
26. Dold U, Edler L, Mäurer HCh, et al., eds.: [Adjuvant Cancer Therapy in Advanced Non-Small Cell Bronchial Cancer: Multicentric Controlled Studies To Test the Efficacy of Iscador and Polyerga]. Georg Thieme Verlag, 1991.
27. Longhi A, Reif M, Mariani E, et al.: A Randomized Study on Postrelapse Disease-Free Survival with Adjuvant Mistletoe versus Oral Etoposide in Osteosarcoma Patients. Evid Based Complement Alternat Med 2014: 210198, 2014. [PUBMED Abstract]
28. Augustin M, Bock PR, Hanisch J, et al.: Safety and efficacy of the long-term adjuvant treatment of primary intermediate- to high-risk malignant melanoma (UICC/AJCC stage II and III) with a standardized fermented European mistletoe (Viscum album L.) extract. Results from a multicenter, comparative, epidemiological cohort study in Germany and Switzerland. Arzneimittelforschung 55 (1): 38-49, 2005. [PUBMED Abstract]
29. Bock PR, Friedel WE, Hanisch J, et al.: Retrolective, comparative, epidemiological cohort study with parallel groups design for evaluation of efficacy and safety of drugs with "well-established use". Forsch Komplementarmed Klass Naturheilkd 11 (Suppl 1): 23-9, 2004. [PUBMED Abstract]
30. Bock PR, Friedel WE, Hanisch J, et al.: [Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma. Results of a multi-center, comparative, epidemiological cohort study in Germany and Switzerland] Arzneimittelforschung 54 (8): 456-66, 2004. [PUBMED Abstract]
31. Klopp R, Schmidt W, Werner E, et al.: Influence of complementary Viscum album (Iscador) administration on microcirculation and immune system of ear, nose and throat carcinoma patients treated with radiation and chemotherapy. Anticancer Res 25 (1B): 601-10, 2005 Jan-Feb. [PUBMED Abstract]
32. Ostermann T, Appelbaum S, Poier D, et al.: A Systematic Review and Meta-Analysis on the Survival of Cancer Patients Treated with a Fermented Viscum album L. Extract (Iscador): An Update of Findings. Complement Med Res 27 (4): 260-271, 2020. [PUBMED Abstract]
33. 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 7 (4): 137-45, 2009. [PUBMED Abstract]
34. Zaenker KS, Matthes H, Bock PR, et al.: A specific mistletoe preparation (Iscador-Qu) in colorectal cancer (CRC) patients: more than just supportive care? Journal of Cancer Science & Therapy 4 (9): 264–270, 2012.
35. Salzer G, Danmayr E, Wutzholfer F, et al.: [Adjuvant Iscador® treatment of non-small cell bronchial carcinoma. Results of a randomized study]. Dtsch Z Onkol 23 (4): 93-8, 1991.
36. Longhi A, Cesari M, Serra M, et al.: Long-Term Follow-up of a Randomized Study of Oral Etoposide versus Viscum album Fermentatum Pini as Maintenance Therapy in Osteosarcoma Patients in Complete Surgical Remission after Second Relapse. Sarcoma 2020: 8260730, 2020. [PUBMED Abstract]
37. Tröger 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 49 (18): 3788-97, 2013. [PUBMED Abstract]
38. Hohneck AL, Sadikaj L, Heinemann L, et al.: Patients with Advanced Pancreatic Cancer Treated with Mistletoe and Hyperthermia in Addition to Palliative Chemotherapy: A Retrospective Single-Center Analysis. Cancers (Basel) 15 (20): , 2023. [PUBMED Abstract]
39. Schaefermeyer G, Schaefermeyer H: Treatment of pancreatic cancer with Viscum album (Iscador): a retrospective study of 292 patients 1986-1996. Complement Ther Med 6 (4): 172-7, 1998.
40. Tröger 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 111 (29-30): 493-502, 33 p following 502, 2014. [PUBMED Abstract]
41. Pelzer F, Tröger W, Nat DR: Complementary Treatment with Mistletoe Extracts During Chemotherapy: Safety, Neutropenia, Fever, and Quality of Life Assessed in a Randomized Study. J Altern Complement Med 24 (9-10): 954-961, 2018 Sep/Oct. [PUBMED Abstract]
42. Paller CJ, Wang L, Fu W, et al.: Phase I Trial of Intravenous Mistletoe Extract in Advanced Cancer. Cancer Res Commun 3 (2): 338-346, 2023. [PUBMED Abstract]
43. Piao BK, Wang YX, Xie GR, et al.: Impact of complementary mistletoe extract treatment on quality of life in breast, ovarian and non-small cell lung cancer patients. A prospective randomized controlled clinical trial. Anticancer Res 24 (1): 303-9, 2004 Jan-Feb. [PUBMED Abstract]
44. Lee YG, Jung I, Koo DH, et al.: Efficacy and safety of Viscum album extract (Helixor-M) to treat malignant pleural effusion in patients with lung cancer. Support Care Cancer 27 (5): 1945-1949, 2019. [PUBMED Abstract]
45. Gutsch J, Berger H, Scholz G, et al.: [Prospective study in radically operated breast cancer with polychemotherapy, Helixor® and untreated controls]. Dtsch Z Onkol 21: 94-101, 1988.
46. Douwes FR, Wolfrum DI, Migeod F: [Results of a prospective randomized study: chemotherapy versus chemotherapy plus "biological response modifier" in metastasizing colorectal carcinoma]. Dtsch Z Onkol 18 (6): 155-64, 1986.
47. Eisenbraun J, Scheer R, Kröz M, et al.: Quality of life in breast cancer patients during chemotherapy and concurrent therapy with a mistletoe extract. Phytomedicine 18 (2-3): 151-7, 2011. [PUBMED Abstract]
48. Kim KC, Yook JH, Eisenbraun J, et al.: Quality of life, immunomodulation and safety of adjuvant mistletoe treatment in patients with gastric carcinoma - a randomized, controlled pilot study. BMC Complement Altern Med 12: 172, 2012. [PUBMED Abstract]
49. Cho JS, Na KJ, Lee Y, et al.: Chemical Pleurodesis Using Mistletoe Extraction (ABNOVAviscum(®) Injection) for Malignant Pleural Effusion. Ann Thorac Cardiovasc Surg 22 (1): 20-6, 2016. [PUBMED Abstract]
50. Bar-Sela G, Haim N: Abnoba-viscum (mistletoe extract) in metastatic colorectal carcinoma resistant to 5-fluorouracil and leucovorin-based chemotherapy. Med Oncol 21 (3): 251-4, 2004. [PUBMED Abstract]
51. 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 194 (4): 939-43, 2015. [PUBMED Abstract]
52. Heiny BM, Albrecht V, Beuth J: Stabilization of quality of life with mistletoe lectin-1-standardized extract in advanced colorectal carcinoma. Onkologe 4 (Suppl 1): S35-9, 1998.
53. Sauer H: Quality of life stabilization with mistletoe-1-standardized extract in advanced colorectal carcinoma [Letter]. Onkologe 4: 1180, 1998.
54. Schumacher K, Schneider B, Reich G, et al.: Influence of postoperative complementary treatment with lectin-standardized mistletoe extract on breast cancer patients. A controlled epidemiological multicentric retrolective cohort study. Anticancer Res 23 (6D): 5081-7, 2003 Nov-Dec. [PUBMED Abstract]
55. Enesel MB, Acalovschi I, Grosu V, et al.: Perioperative application of the Viscum album extract Isorel in digestive tract cancer patients. Anticancer Res 25 (6C): 4583-90, 2005 Nov-Dec. [PUBMED Abstract]
56. Cazacu M, Oniu T, Lungoci C, et al.: The influence of isorel on the advanced colorectal cancer. Cancer Biother Radiopharm 18 (1): 27-34, 2003. [PUBMED Abstract]
57. Semiglasov VF, Stepula VV, Dudov A, et al.: The standardised mistletoe extract PS76A2 improves QoL in patients with breast cancer receiving adjuvant CMF chemotherapy: a randomised, placebo-controlled, double-blind, multicentre clinical trial. Anticancer Res 24 (2C): 1293-302, 2004 Mar-Apr. [PUBMED Abstract]
58. Semiglazov VF, Stepula VV, Dudov A, et al.: Quality of life is improved in breast cancer patients by Standardised Mistletoe Extract PS76A2 during chemotherapy and follow-up: a randomised, placebo-controlled, double-blind, multicentre clinical trial. Anticancer Res 26 (2B): 1519-29, 2006 Mar-Apr. [PUBMED Abstract]
59. Freuding M, Keinki C, Kutschan S, et al.: Mistletoe in oncological treatment: a systematic review : Part 2: quality of life and toxicity of cancer treatment. J Cancer Res Clin Oncol 145 (4): 927-939, 2019. [PUBMED Abstract]
60. Loef M, Walach H: Quality of life in cancer patients treated with mistletoe: a systematic review and meta-analysis. BMC Complement Med Ther 20 (1): 227, 2020. [PUBMED Abstract]
61. 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 16 (4): 217-26, 2009. [PUBMED Abstract]
62. Freuding M, Keinki C, Micke O, et al.: Mistletoe in oncological treatment: a systematic review : Part 1: survival and safety. J Cancer Res Clin Oncol 145 (3): 695-707, 2019. [PUBMED Abstract]
63. Lenartz D, Stoffel B, Menzel J, et al.: Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients. Anticancer Res 16 (6B): 3799-802, 1996 Nov-Dec. [PUBMED Abstract]

Although a number of different mistletoe extracts have been used in human studies, the reported side effects have generally been minimal and not life threatening. Common side effects include the following:[1-4]

One meta-analysis using Viscum album L. and isolated mistletoe lectins included both animal and human studies. Doses and application forms varied. No immunosuppressive effects were reported. Side effects included local reactions at the injection site and flu-like symptoms such as fever, chills, fatigue, mild gastrointestinal symptoms, and headache. High doses of recombinantly-produced mistletoe lectins (not available in commercial products) resulted in reversible hepatotoxicity in some cases.[5] Another review reported adverse reactions that included local reactions at the injection site, fever, increased intracerebral pressure, headache, circulatory problems, thrombophlebitis, swelling of lymph nodes, and allergic reactions.[6]

A few cases of severe allergic reactions, including anaphylactic shock, have been reported.[2]

Although from an observational cohort study, three types of mistletoe (Iscador, Helixor, and abnobaVISCUM) that were given intratumorally, intravenously, or subcutaneously were found to be safe in a small group of cancer patients with autoimmune diseases such as Graves disease, Hashimoto thyroiditis, ulcerative colitis, psoriasis, and some rheumatic diseases.[7]

References

1. Kaegi E: Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. CMAJ 158 (9): 1157-9, 1998. [PUBMED Abstract]
2. Hutt N, Kopferschmitt-Kubler M, Cabalion J, et al.: Anaphylactic reactions after therapeutic injection of mistletoe (Viscum album L.). Allergol Immunopathol (Madr) 29 (5): 201-3, 2001 Sep-Oct. [PUBMED Abstract]
3. Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002. [PUBMED Abstract]
4. Steele ML, Axtner J, Happe A, et al.: Safety of Intravenous Application of Mistletoe (Viscum album L.) Preparations in Oncology: An Observational Study. Evid Based Complement Alternat Med 2014: 236310, 2014. [PUBMED Abstract]
5. Kienle GS, Grugel R, Kiene H: Safety of higher dosages of Viscum album L. in animals and humans--systematic review of immune changes and safety parameters. BMC Complement Altern Med 11: 72, 2011. [PUBMED Abstract]
6. Ernst E, Schmidt K, Steuer-Vogt MK: Mistletoe for cancer? A systematic review of randomised clinical trials. Int J Cancer 107 (2): 262-7, 2003. [PUBMED Abstract]
7. Oei SL, Thronicke A, Kröz M, et al.: Use and Safety of Viscum album L Applications in Cancer Patients With Preexisting Autoimmune Diseases: Findings From the Network Oncology Study. Integr Cancer Ther 18: 1534735419832367, 2019 Jan-Dec. [PUBMED Abstract]

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the levels of evidence) associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For an explanation of the scores and additional information about levels of evidence analysis for cancer, see Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

Mistletoe is one of the most widely studied complementary and alternative medicine therapies for cancer. In certain European countries, the preparations made from European mistletoe (Viscum album L.) are among the most prescribed drugs offered to cancer patients. Mistletoe extracts have been evaluated in numerous clinical studies and improvements in survival, quality of life, and/or stimulation of the immune system have been frequently reported. However, most clinical studies conducted have had one or more major weaknesses that raise doubts about the reliability of the findings. In addition, no evidence exists to support the notion that stimulation of the immune system by mistletoe leads to an improved ability to fight cancer. Because all patients in the reported clinical studies appear to have been adults, no information is available about the use of mistletoe as a treatment for children with cancer.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information

Revised text to state that although the U.S. Food and Drug Administration has regulatory authority over homeopathic drugs, this authority is usually not exercised unless the drugs are formulated for injection, such as the mistletoe product described in this summary.

Human/Clinical Studies

Added text about a retrospective analysis that investigated the effects of mistletoe and chemotherapy with hyperthermia versus mistletoe and chemotherapy in the palliative treatment of patients with pancreatic cancer. The results of the analysis found a significant improvement in survival rates in the patients who received all three treatments. Weaknesses of the analysis include the retrospective nature of the study, multiple types of chemotherapy and mistletoe regimens used, and the lack of a a study arm for hyperthermia and chemotherapy (cited Hohneck et al. as reference 38). Furthermore, the study was not stratified despite enrolling patients who were previously treated with 1 to 3 lines of therapy, making the group median survival rates clinically insignificant.

Revised Table 3 to include the Hohneck et al. study in the use of Iscador in cancer treatment: clinical reports describing therapeutic end points.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.