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Mistletoe Extracts (PDQ®): Complementary and alternative medicine - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Mistletoe Extracts

Overview

This complementary and alternative medicine (CAM) 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:

  • Mistletoe is a semiparasitic plant that has been used for centuries to treat numerous human ailments.
  • Mistletoe is used commonly in Europe, where a variety of different extracts are manufactured and marketed as injectable prescription drugs. These injectable drugs are not available commercially in the United States and are not approved as a treatment for people with cancer.
  • Mistletoe is one of the most widely studied CAM therapies for cancer. In certain European countries, the preparations made from European mistletoe (Viscum album, Loranthaceae) are among the most prescribed drugs offered to cancer patients.[1]
  • Although mistletoe plants and berries are considered poisonous to humans, few serious side effects have been associated with mistletoe extract use.
  • The use of mistletoe as a treatment for people with cancer has been investigated in clinical studies. Reports of improved survival and/or quality of life have been common, but nearly all of the studies had major weaknesses that raise doubts about the reliability of the findings.
  • At present, the use of mistletoe cannot be recommended outside the context of well-designed clinical trials. Such trials will be valuable to determine more clearly whether mistletoe can be useful in the treatment of specific subsets of cancer patients.

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 CAM information summaries may include links to external Web sites 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 Web sites, or of any treatment or product, by the PDQ Cancer CAM Editorial Board or the National Cancer Institute.

References:

1. Horneber MA, Bueschel G, Huber R, et al.: Mistletoe therapy in oncology. Cochrane Database Syst Rev (2): CD003297, 2008.

General Information

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[1,2,3,4,5,6,7,8] Reviewed in [9,10] and to stimulate immune system cells both in vitro and in vivo.[11,12,13,14,15,16,17,18,19] Reviewed in [10,20,21,22,23,24] Two components of mistletoe, namely viscotoxins and lectins, may be responsible for these effects.[11,12,13,17,18,19,25,26,27,28,29,30,31] Reviewed in [10,21,22,23,32] Viscotoxins are small proteins that exhibit cell-killing activity and possible immune-system-stimulating activity.[1,6,18,19] Reviewed in [33,34] 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. Reviewed in [10,35,36,37,38] In view of mistletoe's ability to stimulate the immune system, it has been classified as a type of biological response modifier. Reviewed in [35] 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.[39]

Preparations from mistletoe extracts are most frequently used in the treatment of cancer patients in German-speaking countries.[40] 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.

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 cytoxocity in laboratory studies.[41,42,43,44,45]

Mistletoe grows on several types of trees, and the chemical composition of extracts derived from it depends on the species of the host tree (e.g., apple, elm, oak, pine, poplar, and spruce), the time of year harvested, how the extracts are prepared, and the commercial producer.[46,47] Reviewed in [8,36,48,49]

Mistletoe extracts are prepared as aqueous solutions or solutions of water and alcohol, and they can be fermented or unfermented.[6,46] Reviewed in [4,20,47,50,51,52,53] Some extracts are prepared according to homeopathic principles, and others are not. Accordingly, as homeopathic preparations, they are typically not chemically standardized extracts. Reviewed in [10,54] 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 IscadorM (from apple trees; Malus domestica), IscadorP (from pine trees; Pinus sylvestris), IscadorQ (from oak trees; Quercus robur), and IscadorU (from elm trees; Ulmus minor). 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 HelixorA (from spruce trees; Picea abies), HelixorM (from apple trees), and HelixorP (from pine trees; Pinus sylvestris). Reviewed in [51] Eurixor, 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; refer to the History section of this summary for more information). Reviewed in [51] Some proponents contend the choice of extract should depend on the type of tumor and the gender of the patient.[55] Reviewed in [49,51,56]

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. Since this is not an extract of mistletoe, it is out of the purview of this summary.[57]

Mistletoe extracts are usually given by subcutaneous injection, although administration by other routes (i.e., oral, intrapleural, intratumoral, and intravenous) has been described.[17,21,22,23,32,58,59,60,61,62,63] Reviewed in [20,24,36,49,51,54] 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.[64] 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 or there is evidence of severe toxicity. At present, the FDA does not allow the importation or distribution of injectable preparations of mistletoe, including homeopathic formulations, except for the purpose of clinical research. The extracts are not available commercially in the United States and are not approved as a treatment for people with cancer.

Before researchers can conduct clinical drug research in the United States, they must file an Investigational New Drug (IND) application with the FDA. IND approval is also required for clinical investigation of homeopathic drugs. The FDA does not disclose information about IND applications or approvals; this information can be released only by the applicants. At least two U.S. investigators were given IND approval to study mistletoe as a treatment for people with cancer (NCCAM-02-AT-260 and TJUH-01F.45). The final clinical trial results have not been reported.

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.
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.
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.
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.
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.
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.
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.
9. Franz H: Mistletoe lectins and their A and B chains. Oncology 43 (Suppl 1): 23-34, 1986.
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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. Mistletoe. In: Murray MT: The Healing Power of Herbs. Roseville, Calif: Prima Publishing, 1995, pp 253-9.
21. 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.
22. 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.
23. 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.
24. 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.
25. Frohne D, Pfander HJ: Viscum album. In: Frohne D, Pfander HJ: Giftpflanzen: ein Handbuch für Apotheker, Ärzte, Toxikologen und Biologen. 3rd rev. ed. Stuttgart, Germany: Wissenschaftliche Verlagsgesellschaft, 1987, pp 179-80.
26. 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. Brussels, Belgium: European Commission, Directorate-General XII, Science, Research and Development, 1998, pp 164-7.
27. 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.
28. 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. Brussels, Belgium: European Commission, Directorate-General XII, Science, Research and Development, 1998, pp 221-5.
29. 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. Brussels, Belgium: European Commission, Directorate-General XII, Science, Research and Development, 1998, pp 215-20.
30. Tubeuf KFv, Neckel G, Marzell H: Monographie der Mistel. Munchen, Berlin: R. Oldenbourg, 1923.
31. Teuscher E: Viscum album. In: Hansel R, Keller K, Rimpler H, et al.: Hagers Handbuch der Pharmazeutischen Praxis, Vol. 6. 5th ed. Berlin, Germany: Springer-Verlag, 1994, pp 1160-83.
32. 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.
33. Capernaros Z: The golden bough: the case for mistletoe. Eur J Herbal Med 1 (1):19-24, 1994.
34. Schrader G, Apel K: Isolation and characterization of cDNAs encoding viscotoxins of mistletoe (Viscum album). Eur J Biochem 198 (3): 549-53, 1991.
35. 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.
36. Samtleben R, Hajto T, Hostanska K, et al.: Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic). In: Wagner H, ed.: Immunomodulatory Agents from Plants. Basel, Switzerland: Birkhauser Verlag, 1999, pp 223-41.
37. Abdullaev FI, de Mejia EG: Antitumor effect of plant lectins. Nat Toxins 5 (4): 157-63, 1997.
38. Kilpatrick DC: Mechanisms and assessment of lectin-mediated mitogenesis. Mol Biotechnol 11 (1): 55-65, 1999.
39. 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.
40. Horneber MA, Bueschel G, Huber R, et al.: Mistletoe therapy in oncology. Cochrane Database Syst Rev (2): CD003297, 2008.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.
47. Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995.
48. Zee-Cheng RK: Anticancer research on Loranthaceae plants. Drugs Future 22 (5): 519-30, 1997.
49. 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.
50. 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.
51. Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994.
52. Wagner H, Jordan E, Feil B: Studies on the standardization of mistletoe preparations. Oncology 43 (Suppl 1): 16-22, 1986.
53. 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.
54. Mellor D: Mistletoe in homoeopathic cancer treatment. Prof Nurse 4 (12): 605-7, 1989.
55. 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.
56. 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.
57. 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.
58. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. 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.
64. Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States.: Homoeopathic Pharmacopoeia of the United States. Washington, DC: 2002, Monograph 9444 Visc.

History

Mistletoe has been used for centuries for its medicinal properties. Reviewed in [1,2,3,4,5,6] 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. Modern interest in mistletoe as an anticancer treatment began in the 1920s. Reports of more than 30 clinical studies of mistletoe as a treatment for people with cancer have been published since the early 1960s.[7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36] Reviewed in [3,37,38] Most of the results of these studies were published exclusively in German. (Refer to the Human/Clinical Studies section of this summary for more information.)

As indicated previously (refer to the General Information section of this summary for more information), proposed mechanisms of action for mistletoe that are relevant to cancer include stimulation of the immune system [7,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68] Reviewed in [1,2,3,8,9,10,11,37,38,69,70,71,72] and a direct toxic effect on tumor cells.[73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89] Reviewed in [1,69,71,90]. Another reported activity 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.[91,92,93,94] Reviewed in [95]

Mistletoe has been shown to stimulate increases in the number and the activity of various types of white blood cells.[7,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68] Reviewed in [2,3,8,9,11,29,38,69,70,71,72,93,95,96,97,98] 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.[42,47,57,61,64] Reviewed in [1,3,8,11,29,37,38,69,70,71,72,91,93,94,95,96,98] Other evidence suggests that mistletoe exerts its cytotoxic effects by interfering with protein synthesis in target cells [4,73,81,90,99] Reviewed in [3,8,61,69,70,71,72,79,86,89,92,95,98,100,101] and by inducing apoptosis.[83,95,102] Reviewed in [3,63,69,72,87,98] Mistletoe may also serve a bridging function, bringing together immune system effector cells and tumor cells.[46,103]

More information about the immune system and how it works.

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. Roseville, Calif: 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. Basel, Switzerland: 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.
5. Becker H: Botany of European mistletoe (Viscum album L.). Oncology 43 (Suppl 1): 2-7, 1986.
6. Watkins D: A berry Christmas. Nurs Times 93 (51): 28-9, 1997 Dec 17-23.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Friess H, Beger HG, Kunz J, et al.: Treatment of advanced pancreatic cancer with mistletoe: results of a pilot trial. Anticancer Res 16 (2): 915-20, 1996 Mar-Apr.
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 7 (3): 57-66, 68-72, 74-6 passim, 2001 May-Jun.
14. 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.
15. 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.
16. Majewski A, Bentele W: [Adjunct treatment in female genital carcinoma]. Zentralbl Gynakol 20: 696-700, 1963.
17. Fellmer Ch, Fellmer KE: [Follow-up treatment of irradiated genital carcinoma with the Viscum album preparation "Iscador"]. Krebsarzt 2: 175-85, 1966.
18. Leroi R: [Studies on additional Iscador therapy in the management of women with surgically and radiotherapeutically treated genital carcinoma] Gynaecologia 167 (3): 158-70, 1969.
19. Leroi R: [Postoperative Viscum album therapy after surgery of breast neoplasms] Helv Chir Acta 44 (3): 403-14, 1977.
20. Salzer G, Havelec L: [Prevention of recurrence of bronchial carcinomas after surgery by means of the mistletoe extract Iscador. Results of a clinical study from 1969-1971] Onkologie 1 (6): 264-7, 1978.
21. Salzer G, Denck H: [Randomized study on medicamentous recurrence prophylaxis with 5-fluorouracil and Iscador in resectioned stomach cancer. Results of an intermediate assessment]. Dtsch Z Onkol 11 (5): 130-1, 1979.
22. Salzer G: Pleura carcinosis. Cytomorphological findings with the mistletoe preparation iscador and other pharmaceuticals. Oncology 43 (Suppl 1): 66-70, 1986.
23. 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.
24. Douwes FR, Kalden M, Frank G, et al.: [Treatment of advanced colorectal carcinoma: efficacy test of the combination of 5-fluorouracil and tetrahydrofolic acid versus 5-fluorouracil and tetrahydrofolic acid in combination with an optimized Helixor treatment]. Dtsch Z Onkol 21 (3): 63-7, 1988.
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37. Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994.
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39. Nienhaus J, Stoll M, Vester F: Thymus stimulation and cancer prophylaxis by Viscum proteins. Experientia 26 (5): 523-5, 1970.
40. 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.
41. 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.
42. Hajto T: Immunomodulatory effects of iscador: a Viscum album preparation. Oncology 43 (Suppl 1): 51-65, 1986.
43. 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.
44. 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.
45. 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.
46. 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.
47. 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.
48. 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.
49. 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.
50. Kuttan G, Kuttan R: Immunomodulatory activity of a peptide isolated from Viscum album extract (NSC 635 089). Immunol Invest 21 (4): 285-96, 1992.
51. 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.
52. 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.
53. 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.
54. 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.
55. Kuttan G: Tumoricidal activity of mouse peritoneal macrophages treated with Viscum album extract. Immunol Invest 22 (6-7): 431-40, 1993 Aug-Oct.
56. 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.
57. 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.
58. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. 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.
64. 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.
65. 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.
66. 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.
67. 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.
68. 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.
69. 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.
70. 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.
71. Zee-Cheng RK: Anticancer research on Loranthaceae plants. Drugs Future 22 (5): 519-30, 1997.
72. 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.
73. 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.
74. 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.
75. Ribéreau-Gayon G, Jung ML, Baudino S, et al.: Effects of mistletoe (Viscum album L.) extracts on cultured tumor cells. Experientia 42 (6): 594-9, 1986.
76. 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.
77. Hülsen H, Mechelke F: In vitro effectiveness of a mistletoe preparation on cytostatic-drug-resistant human leukemia cells. Naturwissenschaften 74 (3): 144-5, 1987.
78. Kuttan G, Vasudevan DM, Kuttan R: Isolation and identification of a tumour reducing component from mistletoe extract (Iscador). Cancer Lett 41 (3): 307-14, 1988.
79. 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.
80. 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.
81. 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.
82. Gawlik C, Versteeg R, Engel E, et al.: Antiproliferative effect of mistleotoe-extracts in melanoma cell lines. [Abstract] Anticancer Res 12 (6A): A-364, 1882, 1992.
83. 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.
84. 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.
85. 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.
86. 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.
87. 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.
88. Holtskog R, Sandvig K, Olsnes S: Characterization of a toxic lectin in Iscador, a mistletoe preparation with alleged cancerostatic properties. Oncology 45 (3): 172-9, 1988.
89. 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.
90. Franz H: Mistletoe lectins and their A and B chains. Oncology 43 (Suppl 1): 23-34, 1986.
91. 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.
92. 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.
93. 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.
94. 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.
95. 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.
96. 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.
97. 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.
98. 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.
99. 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.
100. Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995.
101. 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.
102. 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.
103. 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.

Laboratory / Animal / Preclinical Studies

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; however, most research has focused on the lectins.[1,2,3,4,5,6,7] Reviewed in [8,9] Purified mistletoe lectins have demonstrated cytotoxic and immune-system-stimulating activities. To date, four different lectins: ML-1, ML-2, ML-3, and Viscum albumchitin -binding agglutinin have been identified in mistletoe extracts. 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.[12] Reviewed in [13,14] 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.[1,17,18] Reviewed in [1,6,7,8,9,13] 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.[19,20] Reviewed in [21]

Recombinant ML-1, rML (also known as rViscunim or aviscumin) appears to have the same efficacy as plant-based ML-1 in laboratory studies.[22] Since 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. [17,26,27,28,29,30,31,32] Reviewed in [4,6,8,9,33] In addition, mistletoe extracts have demonstrated cytotoxic activity against a variety of mouse, rat, and human cancer cells in vitro.[1,23,34,35,36,37] Reviewed in [8]

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]

A 2004 in vitro study of IscadorQ, a fermented aqueous extract from European mistletoe grown on oaks, against various cell lines demonstrated that sensitivity to this extract varies greatly among cell lines. In sensitive cell lines, a strong effect was seen in epidermal (HaCaT), lung adenocarcinoma (NCI-H125), and breast adenocarcinoma (MCF-7) cell lines whereas, little or no effect was seen in lung squamous cell carcinoma (MR65) and colon carcinoma (Cac0-2, HT-29). Some cells lines were responsive to high or low concentrations of IscadorQ. IscadorQ showed early cell cycle inhibition followed by apoptosis in a dose-dependent manner.[40]

Studies of the ability of mistletoe to inhibit cancer cell growth in animals have yielded mixed and inconsistent results.[5,6,7,36,41,42,43,44,45,46,47,48] Reviewed in [8,9,49] In most of these studies, mistletoe extracts were administered either by subcutaneous injection or by intraperitoneal injection.

In one animal study, treatment with IscadorM increased the survival time of mice that had been implanted with Ehrlich ascites mouse cancer cells, but not L1210 leukemia or B16 melanoma cancer cells.[50] The effect of IscadorM on the growth of tumors formed in mice by three additional types of mouse cancer cells (i.e., Lewis lung carcinoma, colon adenocarcinoma 38, and C3H mammary adenocarcinoma) was also assessed in this study. Treatment with IscadorM substantially reduced the growth rate of all three types of tumors.

In another animal study, mice were administered IscadorM before, during, or after injection with either of two types of mouse cancer cells (i.e., Dalton lymphoma or Ehrlich ascites).[51] In this study, all groups of mice treated with mistletoe showed substantially slower tumor growth than the control groups.

No antitumor effect or improvement in survival was observed when IscadorM was used to treat rats bearing chemically induced mammary carcinomas or tumors formed from rat Walker 256 carcinosarcoma cells.[52] In this study, IscadorM was also not effective in treating mice that had been injected with Ehrlich ascites cells. In addition, IscadorP was found ineffective in treating rats with tumors formed from rat L5222 leukemia cells.

In another study, intratumoral injections of mistletoe extract (abnobaVISCUM Fraxini-2) demonstrated more antitumor activity than intravenous gemcitabine when injected into mouse xenografts of human pancreatic cancer.[53]

Treatment with the mistletoe extract Lektinol (also sold as Plenosol; refer to the General Information section of this summary for more information) has likewise yielded mixed results in animal experiments.[7] Treatment with Lektinol slowed the growth of tumors formed in mice from implants of three types of mouse cancer (i.e., colon adenocarcinoma 38, Renca renal cell carcinoma, and F9 testicular carcinoma) but not in two other mouse cancers (i.e., B16 melanoma and Lewis lung carcinoma).

The anticancer effects of Isorel (also sold as Vysorel; refer to the General Information section of this summary for more information) have been examined in at least two animal studies.[36,54] In one study, IsorelM was used alone or in combination with local x-ray therapy in mice bearing mouse CMC-2 fibrosarcoma tumors.[54] When IsorelM was used alone, no effect on either tumor growth or animal survival was observed. When IsorelM injections were combined with local x-ray therapy of tumors, substantial improvements in survival were found in comparison with the survival of mice treated with local x-ray therapy alone. With local x-ray therapy alone, 22% of mice were cured of their tumors. When local x-ray therapy was combined with IsorelM injections, administered before or after the x-ray treatment, the cure rate increased to 43%. When IsorelM was administered both before and after local x-ray therapy, the proportion of cured mice increased to 67%.

In another study, IsorelM showed antitumor and antimetastatic effects in mice that had been injected with mouse mammary carcinoma cells.[36] The antitumor effects appeared most pronounced when IsorelM was injected in the vicinity of tumors.

The ability of purified or recombinant lectin ML-1 to inhibit the formation of chemically induced bladder tumors in rats has been evaluated in three studies.[5,48,55] Reviewed in [8] In two of the studies, purified ML-1 was administered by subcutaneous injection.[5,55] Reviewed in [8] Treatment with ML-1 did not reduce the frequency of bladder tumor formation or increase immune system activity in the bladder wall in either study. In the third study, recombinant ML-1 was introduced directly into the bladder through a process known as intravesical instillation.[48] Reviewed in [8] In this study, the frequency of bladder tumor formation was reduced by approximately 50% in ML-1-treated animals. As in the other two studies, immune system activity in the bladder wall was not increased substantially. It was concluded that the antitumor effect observed in this study was the result of direct cytotoxic action by the recombinant lectin against malignant cells.[48]

A few animal studies have suggested that mistletoe is beneficial in decreasing the side effects of conventional anticancer therapy (e.g., chemotherapy and radiation therapy) and that it counteracts the effects of drugs used to suppress the immune system.[56,57,58] Reviewed in [59] In one study, IscadorM was shown to increase the number of white blood cells in mice treated with cyclophosphamide chemotherapy or radiation therapy and to decrease the amount of weight loss due to radiation, but not during cyclophosphamide treatment.[58] In another study, IscadorM was shown to accelerate the recovery of hematopoietic tissue in the bone marrow and spleens of irradiated rats and mice.[56] In another study, the mistletoe product Eurixor was shown to counteract the immunosuppressive effects of treatment with the drug cortisone.[57]

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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.
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.
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.
22. Habeck M: Mistletoe compound enters clinical trials. Drug Discov Today 8 (2): 52-3, 2003.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
33. Hallek M: Interleukin-6-mediated cell growth in multiple myeloma--a role for Viscum album extracts? Onkologie 28 (8-9): 387, 2005.
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.
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.
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.
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.
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.
40. Harmsma M, Grommé M, Ummelen M, et al.: Differential effects of Viscum album extract IscadorQu on cell cycle progression and apoptosis in cancer cells. Int J Oncol 25 (6): 1521-9, 2004.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.
47. 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.
48. 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.
49. 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.
50. 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.
51. 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.
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.
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.
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.
55. 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.
56. 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.
57. 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.
58. Kuttan G, Kuttan R: Reduction of leukopenia in mice by "viscum album" administration during radiation and chemotherapy. Tumori 79 (1): 74-6, 1993.
59. Zee-Cheng RK: Anticancer research on Loranthaceae plants. Drugs Future 22 (5): 519-30, 1997.

Human / Clinical Studies

Mistletoe has been evaluated as a treatment for people with cancer in numerous clinical studies.[1,2,3,4,5,6,7,8,9,10,11,12,13,14] Reviewed in [15,16,17,18,19,20] One phase II study in Israel involved carboplatin /gemcitabine in combination with mistletoe as a complementary treatment in patients with non-small cell lung cancer (NCT00516022).[21] Most studies have been conducted in Europe, primarily in Germany and Austria. However, in 2002, the National Center for Complementary and Alternative Medicine in cooperation with the National Cancer Institute (NCI) began accruing patients to a phase I trial (NCCAM-02-AT-260) of mistletoe (Helixor A) and gemcitabine in patients with advanced solid tumors. The Helixor A and gemcitabine combination showed limited toxicity with clinical benefit in 48% of patients.[22] The trial is now closed and the data is being analyzed. Another U.S. trial (NCT00283478) of the mistletoe extract Iscar with gemcitabine versus gemcitabine alone as a second-line therapy for non-small cell lung cancer patients who have failed one prior line of chemotherapy has been completed.

The mistletoe extracts and products studied in clinical trials were Iscador, Eurixor, Helixor, Lektinol, Isorel, abnobaVISCUM,[23] and recombinant lectin ML-1 (refer to the tables at the end of this section for more information).

Approximately half of the reported studies were controlled studies, and a majority of these were randomized clinical trials. Survival was the principal endpoint measured in most reported studies; however, other endpoints included tumor response, tumor recurrence, and quality of life. A systematic review of all controlled clinical studies of mistletoe found consistent improvement in chemotherapy-associated fatigue as well as other quality-of-life measures.[24]

Although mistletoe was found to be therapeutically effective in most of the reported studies, many of the studies had one or more major weaknesses that raised doubts about the reliability of the findings. These weaknesses include registration of small numbers of patients; presence of large numbers of patients who either were not evaluable or were otherwise excluded from the analyses; failure to adequately document mistletoe use, mistletoe dose, and/or interruptions of mistletoe use; absence of control subjects or use of historical control subjects; use of inadequate randomization procedures; absence of treatment blinding; extensive use of subset analysis; and the measurement of mean as opposed to median survival. (Note: In studies with small numbers of patients, the mean survival time [i.e., the average survival time] can be greatly exaggerated if one or more patients exhibit unusually long survival; median survival, therefore, is a less biased measure.) 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. A selection of studies is discussed below, organized by the type of mistletoe extract used.

Iscador

A three-arm, randomized phase III trial that involved 408 patients with previously untreated, inoperable non-small cell lung cancer was conducted between 1978 and 1987.[25] Patients were randomly assigned to one of the following treatments: (1) subcutaneous injection 3 times a week with IscadorU or IscadorQ (refer to the General Information section of this summary for more information); the concentration of mistletoe was increased during a seven-injection sequence or cycle, followed by a 3-day pause, and then the process was repeated; IscadorU was administered for two cycles, followed by two cycles of IscadorQ; both mistletoe preparations contained mercury); (2) intramuscular injection once a week with Polyerga Neu, which is a sheep spleen glycopeptide that is reported to be an immunostimulant and an inhibitor of tumor cell glycolysis; and (3) intramuscular injection once a week with a vitamin B mixture, which served as a placebo. Complete follow-up information was available for 337 patients, and 312 patients (105 Iscador treated, 100 Polyerga Neu treated, and 107 placebo treated) were included in the survival analysis. No statistically significant differences in survival were found between the three groups. Median survival for the Iscador group was 9.1 months; for the Polyerga Neu group, it was 9.0 months; and for the placebo group, it was 7.6 months. The researchers reported that 11.5% of the patients in the Iscador group survived 2 years from the time they entered the trial; the corresponding survival values for the Polyerga Neu and the placebo groups were 13.9% and 10.1%, respectively. In addition, no differences were found between the three groups with respect to tumor response, median body weight, blood chemistry values, Karnofsky Performance Status, and quality of life. However, more patients in the Iscador group than in the Polyerga Neu or the placebo groups reported subjective improvement in feelings of well-being (59.4% vs. 43.2% and 44.8%, respectively).

Another randomized phase III trial of mistletoe as a treatment for people with cancer involved 830 patients with high-risk melanoma (i.e., a primary tumor >3 mm in diameter and no regional lymph nodes positive for cancer or a primary tumor of any size, one or two regional lymph nodes positive for cancer, and no distant metastases) who were randomly assigned to one of the following four groups after potentially curative surgery: (1) treatment with low-dose interferon -alpha, (2) treatment with low-dose interferon-gamma, (3) treatment with IscadorM, or (4) no further treatment. Both types of interferon and IscadorM were administered by subcutaneous injection for a period of 1 year.[5] The interferon injections were administered every other day, whereas IscadorM was administered 3 times a week. After 8 years of follow-up, no increase in survival time or increase in time until melanoma recurrence was demonstrated for mistletoe treatment or treatment with either type of interferon. A nonrandomized, case-control study of long-term mistletoe extract for patients with melanoma, however, showed a survival advantage among patients with high-risk disease.[26]

Three other studies of mistletoe were described in a single published report.[4] One of the three studies was a large cohort study on the effectiveness of Iscador as a treatment for people with rectal cancer, colon cancer, breast cancer, stomach cancer, or lung cancer.[4] The second and third studies were small, prospective, randomized, matched-pair studies (one randomized, one nonrandomized) that involved patients who were selected from a group of 8,475 individuals who had not been treated with mistletoe.[4]

These studies are summarized in Table 1. The overall conclusion of the authors in the report of these three studies was that Iscador treatment can produce a clinically significant increase in survival in cancer patients. However, there were several weaknesses in the design and execution of these studies. In a large cohort study, the investigators were unable to find matching cohorts for 61% of eligible patients, and even among the patients for whom matches were found, fewer than two-thirds were judged to adhere strictly to the matching criteria; thus, the final analysis contained fewer than 25% of eligible patients. In the two small prospective studies, no records on the amount or duration of Iscador use were kept.

The use of Iscador as an adjuvant treatment has been examined in several studies. In the following studies, Iscador proved safe and effective and also showed a significant survival advantage over untreated controls.

A retrospective multicenter cohort study of parallel groups examined Iscador as a postoperative adjuvant using safety and efficacy as the main endpoints. A total of 1,442 patient records (710 treated patients and 732 untreated controls) were randomly selected from medical institutions that provided both standard and alternative treatments. Safety and efficacy were measured by the number and severity of adverse drug reactions. The treatment group showed significantly less adverse reactions (confidence interval = 95%; P = < .001) compared with the controls.[27,28]

A multicenter, controlled, retrospective observational cohort study that involved nonmetastatic colorectal cancer patients treated between 1993 and 2002 was conducted to evaluate safety and efficacy measures with Iscador. Eight hundred and four consecutive colorectal patients (429 treated with Iscador and 375 controls) from 26 hospitals and practices were included. Iscador was well tolerated, with a significant reduction in adverse events, a higher rate of symptom relief, and improved disease-free survival compared with the control group. The study concluded the use of Iscador has a beneficial effect as an adjuvant therapy and long-term treatment for patients with stage I to III colorectal cancer.[29]

In another retrospective multicenter cohort study to determine safety and efficacy of Iscador as an adjuvant long-term treatment following surgery for malignant melanoma, 686 patient records were examined (e.g., 357 untreated controls and 329 treated with Iscador). Safety, efficacy, and a cluster of survival endpoints (tumor-related, disease-free, brain-metastases free, and overall survival) were measured. Only mild to intermediate adverse drug reactions were seen in the treated group. Survival analyses showed no evidence of tumor enhancement and no increased incidence of brain or other metastases in the Iscador group. Results suggest significant survival benefit for all survival-related endpoints in the treatment group.[26]

Table 1. Use of Iscador in Cancer Treatment: Clinical Reports Describing Therapeutic Endpointsa

Reference Citation(s) Type of Study Type(s) of Cancer No. of Patients: Enrolled; Treated; Controlb Strongest Benefit Reportedc Concurrent Therapyd Level of Evidence Scoree
LN+ = lymph node–positive disease; No. = number.
a Refer to text and theNCI Dictionary of Cancer Termsfor additional information and definition of terms.
b Number of patients treated plus number of patients controlled may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were administered the treatment being studiedAND for whom results were reported; historical control subjects are not included in number of patients enrolled.
c Strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients.
d Chemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy.
e For information about levels of evidence analysis and an explanation of the level of evidence scores, refer toLevels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.
f Control patients were treated with a vitamin B mixture as a placebo; 100 additional evaluable patients were treated with Polyerga Neu, a sheep spleen glycopeptide reported to be an immunostimulant and an inhibitor of tumor cell glycolysis; treatment with Polyerga Neu was not found to be beneficial.
g Radiation therapy for metastases distant from the site of the primary tumor was permitted; radiation therapy to the primary tumor site or use of other anticancer treatment was not permitted.
h Among 10,226 cancer patients enrolled in a retrospective matched-pair, case-control study, 1,751 had been treated with Iscador or another mistletoe product and 8,475 had not been treated with mistletoe; from the 8,475 untreated patients, two sets of matched pairs were formed for prospective studies; in the prospective studies, one member of each pair was randomly assigned to be treated with Iscador and the other member served as a control subject.
i Patients were strictly matched according to gender, year of birth ± 3 years, year of diagnosis ± 3 years, type of tumor, stage of disease, and conventional therapy received.
[25] Randomized trial Lung, non-small cell, inoperable 408; 105; 107f Subjective improvement in quality of life Yesg 1iiA
[30] Randomized trial Lung, non-small cell, stages I–IV 218; 87; 96 Improved median survival, LN+ patients only No 1iiA
[5] Randomized trial Melanoma, stages II–III 204; 102; 102 None No 1iiA
[27] Comparative, retrolective, cohort study Breast, stages I–IV 1,442; 710; 732 Improved survival Yes 2B
[26] Comparative, retrolective, cohort study Melanoma, stages II–III 686; 329; 357 Improved survival Unknown 2A
[4] Cohort study Breast, stage III 8,475h; 17i; 17i Improved mean survival Yes None
[4] Cohort study Various types, stages I–IV 8,475h; 39i; 39i Improved mean survival Yes None
[4] Cohort study Various types, stages I–IV 10,226h; 396i; 396i Improved mean survival Yes None
[29] Retrospective, observational cohort study Nonmetastatic colorectal 804; 429; 375 Lower incidence of diarrhea, nausea, loss of appetite, dermatitis, fatigue, and mucositis Yes 2C
[31] Nonconsecutive case series Pancreatic 292; 292; various historical controls Improved median survival Yes 3iiiA
[32] Case report Lung, small cell, stage IV 1; 1; None Partial response Yes None

Other Mistletoe Preparations

Eurixor

Five randomized controlled trials of Eurixor have been published as peer-reviewed articles. The largest of these studies involved 477 patients with squamous cell carcinoma of the head and neck.[2] Reviewed in [15] These patients were randomly assigned to treatment with surgery or surgery and radiation therapy, and they were randomly assigned again to either no additional treatment or treatment with Eurixor. This double randomization produced the following four groups: (1) 105 patients treated with surgery alone; (2) 97 patients treated with surgery and Eurixor; (3) 137 patients treated with surgery and radiation therapy; and (4) 138 patients treated with surgery, radiation therapy, and Eurixor. Eurixor was administered in four treatment cycles over a 60-week period. Each treatment cycle lasted 12 weeks and was followed by a 4-week break period. During each cycle, Eurixor was administered by subcutaneous injection twice a week. Each injection contained enough standardized mistletoe extract to yield a dose of 1 nanogram of ML-1 lectin per kilogram of body weight. The results of this randomized trial showed that treatment with Eurixor did not improve either 5-year disease-free survival or 5-year disease-specific survival. In addition, no stimulation of the immune system or improvement in quality of life was found with Eurixor treatment.

It has been suggested that a less-than-optimum dose of mistletoe was administered to patients in this trial.[4] The same dose of Eurixor, however, has been used in other clinical studies, including studies in which benefit was reported.[1,33] In addition, both the dose and the duration of Eurixor treatment in this trial are consistent with those recommended by the manufacturer.[2]

A prospective, randomized phase II trial involved 45 patients who had noninvasive bladder cancer.[3] After surgery, the patients were randomly assigned to receive either three cycles of treatment with Eurixor or no further therapy. The goal of the study was to determine whether Eurixor treatment could reduce bladder cancer recurrence. Twenty-three patients were randomly assigned to the treatment group, and 22 were randomly assigned to the control group. Each cycle of Eurixor treatment consisted of 3 months of subcutaneous injections, administered twice a week, followed by a 3-month break period. One milliliter of Eurixor was administered at each injection. After 18 months of follow-up, 11 recurrences were observed in the treatment group, and 8 were observed in the control group. The average time of recurrence for the treatment group was 6.3 months; for the control group, it was 6.4 months. The median disease-free interval for the treatment group was 9 months; for the control group, it was 10.5 months. None of these differences was considered significant.

A major concern about this study, however, is that the dose of lectin ML-1 administered to patients was not adjusted for body weight. If different batches of Eurixor were used for individual patients, the patients may not have received uniform doses throughout the trial. Each milliliter of Eurixor has been reported to contain 50 to 70 nanograms of ML-1. Reviewed in [1,33,34] Therefore, the dose of lectin administered to a person weighing 120 pounds (approximately 55 kg) could have ranged from 0.91 nanograms per kilogram body weight to 1.27 nanograms per kilogram body weight. For a person weighing 160 pounds (approximately 73 kg), the dose of lectin could have ranged from 0.68 nanograms per kilogram body weight to 0.96 nanograms per kilogram body weight. As indicated above, the manufacturer of Eurixor recommends a dose of 1 nanogram per kilogram body weight. Because 33 of the 45 patients in this trial were men, and men tend to weigh more than women, it is conceivable that a substantial fraction of the patients were treated with lower-than-recommended doses of ML-1.

Isorel

Only two trials of Isorel have been reported in the publicly available, online indexed peer-reviewed medical literature. In one study, 64 patients with advanced colorectal cancer (Dukes C and D) were randomly assigned to three groups: (1) surgery and chemotherapy; (2) surgery and chemotherapy plus Isorel; and (3) surgery alone. Patients receiving treatment with Isorel had a significantly better median survival advantage and a better cumulative survival advantage than patients in the other two groups. In addition there were no side effects to treatment in the Isorel group.[35]

Another study showed that perioperative use of Isorel in patients with cancer of the digestive tract resulted in an increase in lymphocytes through 14 days of drug administration. In a group of 70 surgically treated patients, 40 patients were assigned to the Isorel-treated group, and 30 patients were assigned to the control group. The treatment group showed an increase in CD4/CD8 ratio (P = < .05) from the start to the end of treatment and an increase in natural killer (NK) cell determinants. NK cell activity and lymphocyte levels declined in the controls. Quality-of-life measures also increased in the treatment group.[36]

Helixor

In a three-arm randomized trial, breast cancer patients were randomly assigned to one of the following groups after surgery: Helixor, chemotherapy, or control. Some patients in each group were also treated with local radiation therapy. The number of evaluable patients in the chemotherapy group was 177, with survival in the chemotherapy group superior to that in the control group and equivalent to that in the Helixor group.[37] In another three-arm randomized trial, metastatic colorectal cancer patients were randomly assigned to receive chemotherapy only (n = 20), chemotherapy plus Helixor (n = 20), or chemotherapy plus Ney-Tumorin (n = 20). Ney-Tumorin is a mixture of peptides and proteins from 15 different organs of fetal and young pigs or cows that is reported to have both antitumor and immunostimulatory properties. The mean survival time (in months) of patients treated with either Helixor or Ney-Tumorin was approximately twice that of patients treated with chemotherapy only.[38] The use of Helixor has also been examined in other studies.[39,40,41,42]

abnobaVISCUM

No tumor response was seen in any of the 25 patients in a phase ll trial that examined the effect of a mistletoe extract, known as abnobaVISCUM, in metastatic colorectal cancer resistant to standard treatment (5-fluorouracil and leucovorin chemotherapy). The endpoint of the study was objective tumor response. Patients were administered a gradually increasing daily dose of 0.15 mg to 15 mg. Treatment duration ranged from 4 weeks to 66 weeks. Toxicity levels were mild. Some patients reported relief of disease symptoms.[43] A small, randomized, nonblinded trial of abnobaVISCUM, given postoperatively to 15 patients with resected stage IB or II gastric cancer, showed improved quality of life among patients who received the mistletoe extract compared with 16 untreated controls.[44]

Table 2. Use of Other Mistletoe Products in Cancer Treatment: Clinical Reports Describing Therapeutic Endpointsa

Reference Citation(s) Type of Study Product Tested Type(s) of Cancer No. of Patients: Enrolled; Treated; Controlb Strongest Benefit Reportedc Concurrent Therapyd Level of Evidence Scoree
No. = number.
a Refer to text and theNCI Dictionary of Cancer Termsfor additional information and definition of terms.
b Number of patients treated plus number of patients controlled may not equal number of patients enrolled; number of patients enrolled = number of patients initially recruited/considered by the researchers who conducted a study; number of patients treated = number of enrolled patients who were administered the treatment being studiedAND for whom results were reported; historical control subjects are not included in number of patients enrolled.
c Strongest evidence reported that the treatment under study has anticancer activity or otherwise improves the well-being of cancer patients.
d Chemotherapy, radiation therapy, hormonal therapy, or cytokine therapy administered/allowed at the same time as mistletoe therapy.
e For information about levels of evidence analysis and an explanation of the level of evidence scores, refer toLevels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.
f This trial was a four-arm trial; patients were randomly assigned to surgery only or to surgery plus radiation therapy, followed by a second randomization to no mistletoe treatment or to treatment with Eurixor; the resulting treatment groups contained the following numbers of evaluable patients: surgery only = 105, surgery plus Eurixor = 97, surgery plus radiation therapy = 137, and surgery plus radiation therapy plus Eurixor = 138; radiation therapy and Eurixor treatment overlapped; no treatment approach was superior in terms of disease-free survival, disease-specific survival, improvement in quality of life, or stimulation of the immune system; in the table, mistletoe-treated and nontreated (control) patients were grouped (i.e., number treated = 97 + 138 = 235, and number control = 105 + 137 = 242).
[3] Randomized trial Eurixor Bladder, noninvasive 45; 23; 22 None No 1iiDi
[1,33] Randomized trial Eurixor Brain, glioma; 74% of patients, stages III–IV; 26% of patients, no stage information 47; 20; 18 Improved survival, stages III–IV patients only Yes 1iiA
[45,46] Randomized trial Eurixor Colorectal, metastatic 107; 38; 41 Improved quality of life Yes 1iiA
[2] Randomized trial Eurixor Head and neck, squamous cell, stages I–IV 495; 235f; 242f None Yesf 1iiA
[37] Randomized trial Helixor Breast, stages I–III 692; 192; 274 Improved survival Yes 1iiA
[38] Randomized trial Helixor Colorectal, metastatic 60; 20; 20 Improved mean survival Yes 1iiA
[13] Randomized controlled trial PS76A (Lektin) Breast 352; 176; 176 Improved quality of life Yes 1iC
[35] Randomized trial Isorel Colorectal 64; 50; 14 Improved survival and tolerance to either adjuvant or palliative treatment Yes 1iiA
[36] Nonrandomized controlled trial Isorel Digestive tract 70; 40; 30 Enhanced cellular immunity and improved quality of life No 2C
[43] Nonrandomized controlled trial abnobaVISCUMQuercus Metastatic colorectal 25; 25; none None Yes 2Diii
[23] Nonrandomized controlled trial Viscum fraxini-2 Hepatocellular carcinoma 23; 23; none Improved survival No 2Dii

Current Clinical Trials

Check NCI's list of cancer clinical trials for cancer CAM clinical trials on mistletoe extract that are actively enrolling patients.

General information about clinical trials is also available from the NCI Web site.

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.
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.
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.
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.
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.
6. Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States.: Homoeopathic Pharmacopoeia of the United States. Washington, DC: 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.
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.
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.
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.
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.
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.
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.
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.
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.
18. Horneber MA, Bueschel G, Huber R, et al.: Mistletoe therapy in oncology. Cochrane Database Syst Rev (2): CD003297, 2008.
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.
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.
21. 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.
22. Mansky PJ, Wallerstedt DB, Sannes T, et al.: NCCAM/NCI phase I study of mistletoe extract and gemcitabine in patients with advanced solid tumors. [Abstract] J Clin Oncol 28 (Suppl 15): A-2559, 2010.
23. 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.
24. 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.
25. 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]. Stuttgart, Germany: Georg Thieme Verlag, 1991.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.
31. 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.
32. Bradley GW, Clover A: Apparent response of small cell lung cancer to an extract of mistletoe and homoeopathic treatment. Thorax 44 (12): 1047-8, 1989.
33. 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.
34. Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994.
35. 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.
36. 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.
37. 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.
38. 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.
39. 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.
40. Auerbach L, Dostal V, Václavik-Fleck I, et al.: Signifikant höherer anteil aktivierter NK-Zellen durch additive misteltherapie bei chemotherapierten mamma-Ca-patientinnen in einer prospektiven randomisierten doppelblinden studie. In: Scheer R, Bauer R, Becker H, et al.: Fortschritte in der Misteltherapie. Aktueller Stand der Forschung und klinischen Anwendung. Essen, Germany: KCV-Verlag, 2005, pp 543-54.
41. 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.
42. 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 28 (1B): 523-7, 2008 Jan-Feb.
43. 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.
44. 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.
45. 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.
46. Sauer H: Quality of life stabilization with mistletoe-1-standardized extract in advanced colorectal carcinoma [Letter]. Onkologe 4: 1180, 1998.

Adverse Effects

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 soreness and inflammation at injection sites, headache, fever, and chills. Reviewed in [1,2,3] A few cases of severe allergic reactions, including anaphylactic shock, have been reported.[2]

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.
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.
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.

Summary of the Evidence for Mistletoe Extracts

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 to date 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. At present, there is insufficient evidence to recommend the use of mistletoe as a treatment for people with cancer outside the context of well-designed clinical trials. Such trials will be valuable to determine more clearly whether mistletoe can be useful in the treatment of specific subsets of cancer patients.

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 additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Cancer Complementary and Alternative Medicine.

Changes to This Summary (06 / 07 / 2013)

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.

Human/Clinical Studies

Added Other Mistletoe Preparations as a new subsection.

This summary is written and maintained by the PDQ Cancer Complementary and Alternative Medicine 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 NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of mistletoe extracts in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Complementary and Alternative Medicine Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Mistletoe Extracts are:

  • Lawrence B. Berk, MD, PhD (University of South Florida)
  • John A. Beutler, PhD (National Cancer Institute)

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Complementary and Alternative Medicine Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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National Cancer Institute: PDQ® Mistletoe Extracts. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/cam/mistletoe/HealthProfessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2013-06-07

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