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Mistletoe Extracts - Cancer Trials

Source: Association of Cancer OnLine Resources  www.acor.org and www.cancer.gov (National Cancer Institute)

 

Mistletoe Extracts

 

Overview

This complementary and alternative medicine (CAM) information summary provides an overview of the use of mistletoe as a treatment for 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.

  • Extracts of mistletoe have been shown to kill cancer cells in the laboratory and to stimulate the immune system.

  • Mistletoe is used mainly in Europe, where a variety of different extracts are manufactured and marketed as injectable prescription drugs. These extracts are not available commercially in the United States.

  • 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 cancer has been investigated in more than 30 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 only) to the Cancer.gov Dictionary, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window. All linked terms and their corresponding definitions will appear in a glossary in the printable version of the summary.

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 NCI.

 

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[1-15] Reviewed in [16,17] and to stimulate immune system cells both in vitro and in vivo. [18-48] Reviewed in [17,49-60] Two components of mistletoe, namely viscotoxins and lectins, may be responsible for these effects.[1,4,7,9-11,13,24,26-28,30-33,35,36,38-42,46-48,61-63] Reviewed in [16,17,43,49-52,54-59,64-67] Viscotoxins are small proteins that exhibit cell-killing activity and possible immune- system-stimulating activity.[7,13,47,48] Reviewed in [50,64] Lectins are complex molecules made of both protein and carbohydrates that are capable of binding to the outside of cells (for example, immune system cells) and inducing biochemical changes in them. Reviewed in [17,51,56,68-71] In view of mistletoe’s ability to stimulate the immune system, it has been classified as a type of biological response modifier. Reviewed in [51] 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 is used mainly in Europe, where commercially available extracts are marketed under a variety of brand names, including Iscador, Eurixor, Helixor, Isorel, Iscucin, Plenosol, and ABNOBAviscum. Some extracts are marketed under more than one name. For example, Iscador, Isorel, and Plenosol are also sold as Iscar, Vysorel, and Lektinol, respectively. All of these products are prepared from Viscum album Loranthacea (Viscum album L. or European mistletoe). They are not available commercially in the United States. (See below for more information concerning U.S. availability of these extracts.)

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.[4,72] Reviewed in [15,49,51,52,54-56]

Mistletoe extracts are prepared as aqueous solutions or solutions of water and alcohol, and they can be fermented or unfermented.[4,13] Reviewed in [8,11,20,37,52,53,72-74] Some extracts are prepared according to homeopathic principles, and others are not. Reviewed in [17,75] In addition, the commercial products can be subdivided according to the species of host tree. For example, Iscador, a fermented aqueous extract of Viscum album L. that is prepared as a homeopathic drug, is marketed as IscadorM (from apple trees), IscadorP (from pine trees), IscadorQ (from oak trees), and IscadorU (from elm trees). 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), HelixorM (from apple trees), and HelixorP (from pine trees). Reviewed in [52] 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-I; see History section). Reviewed in [52] Some proponents contend the choice of extract should depend on the type of tumor and the gender of the patient.[76] Reviewed in [52,55,77]

Mistletoe extracts are usually given by subcutaneous injection, although administration by other routes (i.e., oral and intrapleural) has been described.[27,36,42,45,46,51,57-59,65,66,76-94] Reviewed in [52,53,55,56,60,75] 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 (HPUS), which is the officially recognized compendium for homeopathic drugs in this country.[95] Although the 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 FDA has not approved the use of mistletoe as a cancer treatment.

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 present, at least 2 U.S. investigators have IND approval to study mistletoe as a treatment for cancer.[96,97]

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

References

  1. Stirpe F, Sandvig K, Olsnes S, et al.: Action of viscumin, a toxic lectin from mistletoe, on cells in culture. J Biol Chem 257 (22): 13271-7, 1982.  [PUBMED Abstract]

  2. Khwaja TA, Dias CB, Pentecost S: Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids. Oncology 43 Suppl 1:42-50, 1986.  [PUBMED Abstract]

  3. 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.  [PUBMED Abstract]

  4. Ribéreau-Gayon G, Jung ML, Di Scala D, et al.: Comparison of the effects of fermented and unfermented mistletoe preparations on cultured tumor cells. Oncology 43 Suppl 1:35-41, 1986.  [PUBMED Abstract]

  5. Hülsen H, Mechelke F: In vitro effectiveness of a mistletoe preparation on cytostatic-drug-resistant human leukemia cells. Naturwissenschaften 74 (3): 144-5, 1987.  [PUBMED Abstract]

  6. 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.  [PUBMED Abstract]

  7. Jung ML, Baudino S, Ribéreau-Gayon G, et al.: Characterization of cytotoxic proteins from mistletoe (Viscum album L.). Cancer Lett 51 (2): 103-8, 1990.  [PUBMED Abstract]

  8. Kuttan G, Vasudevan DM, Kuttan R: Effect of a preparation from Viscum album on tumor development in vitro and in mice. J Ethnopharmacol 29 (1): 35-41, 1990.  [PUBMED Abstract]

  9. Walzel H, Jonas L, Rosin T, et al.: Relationship between internalization kinetics and cytotoxicity of mistletoe lectin I to L1210 leukaemia cells. Folia Biol (Praha) 36 (3-4): 181-8, 1990.  [PUBMED Abstract]

  10. 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. 

  11. Janssen O, Scheffler A, Kabelitz D: In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis). Arzneimittelforschung 43 (11): 1221-7, 1993.  [PUBMED Abstract]

  12. Jurin M, Zarković N, Hrzenjak M, et al.: Antitumorous and immunomodulatory effects of the Viscum album L. preparation Isorel. Oncology 50 (6): 393-8, 1993 Nov-Dec.  [PUBMED Abstract]

  13. 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. 

  14. Gabius HJ, Darro F, Remmelink M, et al.: Evidence for stimulation of tumor proliferation in cell lines and histotypic cultures by clinically relevant low doses of the galactoside-binding mistletoe lectin, a component of proprietary extracts. Cancer Invest 19 (2): 114-26, 2001.  [PUBMED Abstract]

  15. Maier G, Fiebig HH: Absence of tumor growth stimulation in a panel of 16 human tumor cell lines by mistletoe extracts in vitro. Anticancer Drugs 13 (4): 373-9, 2002.  [PUBMED Abstract]

  16. Franz H: Mistletoe lectins and their A and B chains. Oncology 43 Suppl 1:23-34, 1986.  [PUBMED Abstract]

  17. Mengs U, Göthel D, Leng-Peschlow E: Mistletoe extracts standardized to mistletoe lectins in oncology: review on current status of preclinical research. Anticancer Res 22 (3): 1399-407, 2002 May-Jun.  [PUBMED Abstract]

  18. Nienhaus J, Stoll M, Vester F: Thymus stimulation and cancer prophylaxis by Viscum proteins. Experientia 26 (5): 523-5, 1970.  [PUBMED Abstract]

  19. Rentea R, Lyon E, Hunter R: Biologic properties of iscador: a Viscum album preparation I. Hyperplasia of the thymic cortex and accelerated regeneration of hematopoietic cells following X-irradiation. Lab Invest 44 (1): 43-8, 1981.  [PUBMED Abstract]

  20. Bloksma N, Schmiermann P, de Reuver M, et al.: Stimulation of humoral and cellular immunity by Viscum preparations. Planta Med 46 (4): 221-7, 1982.  [PUBMED Abstract]

  21. Hajto T: Immunomodulatory effects of iscador: a Viscum album preparation. Oncology 43 Suppl 1:51-65, 1986.  [PUBMED Abstract]

  22. Hajto T, Lanzrein C: Natural killer and antibody-dependent cell-mediated cytotoxicity activities and large granular lymphocyte frequencies in Viscum album-treated breast cancer patients. Oncology 43 (2): 93-7, 1986.  [PUBMED Abstract]

  23. Hamprecht K, Handgretinger R, Voetsch W, et al.: Mediation of human NK-activity by components in extracts of Viscum album. Int J Immunopharmacol 9 (2): 199-209, 1987.  [PUBMED Abstract]

  24. Hajto T, Hostanska K, Gabius HJ: Modulatory potency of the beta-galactoside-specific lectin from mistletoe extract (Iscador) on the host defense system in vivo in rabbits and patients. Cancer Res 49 (17): 4803-8, 1989.  [PUBMED Abstract]

  25. Mueller EA, Hamprecht K, Anderer FA: Biochemical characterization of a component in extracts of Viscum album enhancing human NK cytotoxicity. Immunopharmacology 17 (1): 11-8, 1989 Jan-Feb.  [PUBMED Abstract]

  26. Hajto T, Hostanska K, Frei K, et al.: Increased secretion of tumor necrosis factors alpha, interleukin 1, and interleukin 6 by human mononuclear cells exposed to beta-galactoside-specific lectin from clinically applied mistletoe extract. Cancer Res 50 (11): 3322-6, 1990.  [PUBMED Abstract]

  27. Beuth J, Ko HL, Gabius HJ, et al.: Behavior of lymphocyte subsets and expression of activation markers in response to immunotherapy with galactoside-specific lectin from mistletoe in breast cancer patients. Clin Investig 70 (8): 658-61, 1992.  [PUBMED Abstract]

  28. Kuttan G, Kuttan R: Immunological mechanism of action of the tumor reducing peptide from mistletoe extract (NSC 635089) cellular proliferation. Cancer Lett 66 (2): 123-30, 1992.  [PUBMED Abstract]

  29. Kuttan G, Kuttan R: Immunomodulatory activity of a peptide isolated from Viscum album extract (NSC 635 089). Immunol Invest 21 (4): 285-96, 1992.  [PUBMED Abstract]

  30. Gabius HJ, Walzel H, Joshi SS, et al.: The immunomodulatory beta-galactoside-specific lectin from mistletoe: partial sequence analysis, cell and tissue binding, and impact on intracellular biosignalling of monocytic leukemia cells. Anticancer Res 12 (3): 669-75, 1992 May-Jun.  [PUBMED Abstract]

  31. Beuth J, Ko HL, Tunggal L, et al.: Thymocyte proliferation and maturation in response to galactoside-specific mistletoe lectin-1. In Vivo 7 (5): 407-10, 1993 Sep-Oct.  [PUBMED Abstract]

  32. Timoshenko AV, Gabius HJ: Efficient induction of superoxide release from human neutrophils by the galactoside-specific lectin from Viscum album. Biol Chem Hoppe Seyler 374 (4): 237-43, 1993.  [PUBMED Abstract]

  33. Timoshenko AV, Kayser K, Drings P, et al.: Modulation of lectin-triggered superoxide release from neutrophils of tumor patients with and without chemotherapy. Anticancer Res 13 (5C): 1789-92, 1993 Sep-Oct.  [PUBMED Abstract]

  34. Kuttan G: Tumoricidal activity of mouse peritoneal macrophages treated with Viscum album extract. Immunol Invest 22 (6-7): 431-40, 1993 Aug-Oct.  [PUBMED Abstract]

  35. Beuth J, Ko HL, Tunggal L, et al.: Immunoprotective activity of the galactoside-specific mistletoe lectin in cortisone-treated BALB/c-mice. In Vivo 8 (6): 989-92, 1994 Nov-Dec.  [PUBMED Abstract]

  36. Heiny BM, Beuth J: Mistletoe extract standardized for the galactoside-specific lectin (ML-1) induces beta-endorphin release and immunopotentiation in breast cancer patients. Anticancer Res 14 (3B): 1339-42, 1994 May-Jun.  [PUBMED Abstract]

  37. Stein G, Berg PA: Non-lectin component in a fermented extract from Viscum album L. grown on pines induces proliferation of lymphocytes from healthy and allergic individuals in vitro. Eur J Clin Pharmacol 47 (1): 33-8, 1994.  [PUBMED Abstract]

  38. Timoshenko AV, Gabius HJ: Influence of the galactoside-specific lectin from Viscum album and its subunits on cell aggregation and selected intracellular parameters of rat thymocytes. Planta Med 61 (2): 130-3, 1995.  [PUBMED Abstract]

  39. Timoshenko AV, Cherenkevich SN, Gabius HJ: Viscum album agglutinin-induced aggregation of blood cells and the lectin effects on neutrophil function. Biomed Pharmacother 49 (3): 153-8, 1995.  [PUBMED Abstract]

  40. Hostanska K, Hajto T, Spagnoli GC, et al.: A plant lectin derived from Viscum album induces cytokine gene expression and protein production in cultures of human peripheral blood mononuclear cells. Nat Immun 14 (5-6): 295-304, 1995.  [PUBMED Abstract]

  41. Beuth J, Stoffel B, Ko HL, et al.: Immunomodulating ability of galactoside-specific lectin standardized and depleted mistletoe extract. Arzneimittelforschung 45 (11): 1240-2, 1995.  [PUBMED Abstract]

  42. Lenartz D, Stoffel B, Menzel J, et al.: Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients. Anticancer Res 16 (6B): 3799-802, 1996 Nov-Dec.  [PUBMED Abstract]

  43. Fischer S, Scheffler A, Kabelitz D: Oligoclonal in vitro response of CD4 T cells to vesicles of mistletoe extracts in mistletoe-treated cancer patients. Cancer Immunol Immunother 44 (3): 150-6, 1997.  [PUBMED Abstract]

  44. 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: 224-8, 1997. 

  45. 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. Complementary Therapy and Medicine 5 (3): 141-6, 1997. 

  46. Heiny BM, Albrecht V, Beuth J: Correlation of immune cell activities and beta-endorphin release in breast carcinoma patients treated with galactose-specific lectin standardized mistletoe extract. Anticancer Res 18 (1B): 583-6, 1998 Jan-Feb.  [PUBMED Abstract]

  47. Stein GM, Schaller G, Pfüller U, et al.: Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat. Biochim Biophys Acta 1426 (1): 80-90, 1999.  [PUBMED Abstract]

  48. Stein GM, Schaller G, Pfüller U, et al.: Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes. Anticancer Res 19 (2A): 1037-42, 1999 Mar-Apr.  [PUBMED Abstract]

  49. Bocci V: Mistletoe (viscum album) lectins as cytokine inducers and immunoadjuvant in tumor therapy. A review. J Biol Regul Homeost Agents 7 (1): 1-6, 1993 Jan-Mar.  [PUBMED Abstract]

  50. Capernaros Z: The golden bough: the case for mistletoe. Eur J Herbal Med 1 (1):19-24, 1994. 

  51. Gabius HJ, Gabius S, Joshi SS, et al.: From ill-defined extracts to the immunomodulatory lectin: will there be a reason for oncological application of mistletoe? Planta Med 60 (1): 2-7, 1994.  [PUBMED Abstract]

  52. Kleijnen J, Knipschild P: Mistletoe treatment for cancer: review of controlled trials in humans. Phytomedicine 1: 255-60, 1994. 

  53. Mistletoe. In: Murray MT: The Healing Power of Herbs. Roseville, Calif: Prima Publishing, 1995, pp 253-9. 

  54. Zee-Cheng RK: Anticancer research on Loranthaceae plants. Drugs of the Future 22 (5): 519-30, 1997. 

  55. Kaegi E: Unconventional therapies for cancer: 3. Iscador. Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative. CMAJ 158 (9): 1157-9, 1998.  [PUBMED Abstract]

  56. Samtleben R, Hajto T, Hostanska K, et al.: Mistletoe lectins as immunostimulants (chemistry, pharmacology and clinic). In: Wagner H, eds.: Immunomodulatory Agents from Plants. Basel, Switzerland: Birkhauser Verlag, 1999, pp 223-41. 

  57. Lenartz D, Dott U, Menzel J, et al.: Survival of glioma patients after complementary treatment with galactoside-specific lectin from mistletoe. Anticancer Res 20 (3B): 2073-6, 2000 May-Jun.  [PUBMED Abstract]

  58. Steuer-Vogt MK, Bonkowsky V, Ambrosch P, et al.: The effect of an adjuvant mistletoe treatment programme in resected head and neck cancer patients: a randomised controlled clinical trial. Eur J Cancer 37 (1): 23-31, 2001.  [PUBMED Abstract]

  59. Goebell PJ, Otto T, Suhr J, et al.: Evaluation of an unconventional treatment modality with mistletoe lectin to prevent recurrence of superficial bladder cancer: a randomized phase II trial. J Urol 168 (1): 72-5, 2002.  [PUBMED Abstract]

  60. Stauder H, Kreuser ED: Mistletoe extracts standardised in terms of mistletoe lectins (ML I) in oncology: current state of clinical research. Onkologie 25 (4): 374-80, 2002.  [PUBMED Abstract]

  61. Olsnes S, Stirpe F, Sandvig K, et al.: Isolation and characterization of viscumin, a toxic lectin from Viscum album L. (mistletoe). J Biol Chem 257 (22): 13263-70, 1982.  [PUBMED Abstract]

  62. 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.  [PUBMED Abstract]

  63. Dietrich JB, Ribéreau-Gayon G, Jung ML, et al.: Identity of the N-terminal sequences of the three A chains of mistletoe (Viscum album L.) lectins: homology with ricin-like plant toxins and single-chain ribosome-inhibiting proteins. Anticancer Drugs 3 (5): 507-11, 1992.  [PUBMED Abstract]

  64. Schrader G, Apel K: Isolation and characterization of cDNAs encoding viscotoxins of mistletoe (Viscum album). Eur J Biochem 198 (3): 549-53, 1991.  [PUBMED Abstract]

  65. 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.  [PUBMED Abstract]

  66. Grossarth-Maticek R, Kiene H, Baumgartner SM, et al.: Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment: prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Altern Ther Health Med 7 (3): 57-66, 68-72, 74-6 passim, 2001 May-Jun.  [PUBMED Abstract]

  67. Sweeney EC, Palmer RA, Pfüller U: Crystallization of the ribosome inactivating protein ML1 from Viscum album (mistletoe) complexed with beta-D-galactose. J Mol Biol 234 (4): 1279-81, 1993.  [PUBMED Abstract]

  68. Nicolson GL: The interactions of lectins with animal cell surfaces. Int Rev Cytol 39:89-190, 1974.  [PUBMED Abstract]

  69. Barondes SH: Lectins: their multiple endogenous cellular functions. Annu Rev Biochem 50:207-31, 1981.  [PUBMED Abstract]

  70. Abdullaev FI, de Mejia EG: Antitumor effect of plant lectins. Nat Toxins 5 (4): 157-63, 1997.  [PUBMED Abstract]

  71. Kilpatrick DC: Mechanisms and assessment of lectin-mediated mitogenesis. Mol Biotechnol 11 (1): 55-65, 1999.  [PUBMED Abstract]

  72. Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995.  [PUBMED Abstract]

  73. Wagner H, Jordan E, Feil B: Studies on the standardization of mistletoe preparations. Oncology 43 Suppl 1:16-22, 1986.  [PUBMED Abstract]

  74. Zarkovic N, Vukovic T, Loncaric I, et al.: An overview on anticancer activities of the Viscum album extract Isorel. Cancer Biother Radiopharm 16 (1): 55-62, 2001.  [PUBMED Abstract]

  75. Mellor D: Mistletoe in homoeopathic cancer treatment. Prof Nurse 4 (12): 605-7, 1989.  [PUBMED Abstract]

  76. 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. 

  77. Kjaer M: Misteltoe (Iscador) therapy in stage IV renal adenocarcinoma. A phase II study in patients with measurable lung metastases. Acta Oncol 28 (4): 489-94, 1989.  [PUBMED Abstract]

  78. Majewski A, Bentele W: [Adjunct treatment in female genital carcinoma]. Zentralbl Gynakol 20: 696-700, 1963. 

  79. Fellmer Ch, Fellmer KE: [Follow-up treatment of irradiated genital carcinoma with the Viscum album preparation "Iscador"]. Krebsarzt 2: 175-85, 1966. 

  80. 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.  [PUBMED Abstract]

  81. Leroi R: [Postoperative Viscum album therapy after surgery of breast neoplasms] Helv Chir Acta 44 (3): 403-14, 1977.  [PUBMED Abstract]

  82. 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.  [PUBMED Abstract]

  83. 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. 

  84. Salzer G: Pleura carcinosis. Cytomorphological findings with the mistletoe preparation iscador and other pharmaceuticals. Oncology 43 Suppl 1:66-70, 1986.  [PUBMED Abstract]

  85. 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. 

  86. Dowes 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. 

  87. 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. 

  88. 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.  [PUBMED Abstract]

  89. 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. 

  90. Heiny BM: [Adjuvant therapy with standardized mistletoe extract reduces leukopenia and improves the quality of life of patients with advanced breast cancer under palliative chemotherapy (VEC regimen)]. Krebsmedizin 12: 1-14, 1991. 

  91. Schaefermeyer G, Schaefermeyer H: Treatment of pancreatic cancer with Viscum album (Iscador): a retrospective study of 292 patients 1986-1996. Complementary Therapy and Medicine 6: 172-7, 1998. 

  92. 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. 

  93. 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. 

  94. 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. 

  95. Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States: Homoeopathic Pharmacopoeia of the United States. Washington, DC: 2002, Monograph 9444 Visc. 

  96. Mansky P, National Center for Complementary and Alternative Medicine: Phase I Study of Gemcitabine and Mistletoe in Patients With Advanced Solid Tumors , NCCAM-02-AT-260, Clinical trial, Active.  [PDQ Clinical Trial]

  97. Rosenzweig S, Kimmel Cancer Center of Thomas Jefferson University - Philadelphia: Phase II Study of Supplemental Treatment With Mistletoe in Patients With Stage IV Non-Small Cell Lung Cancer Receiving Palliative Chemotherapy , TJUH-01F.45, Clinical trial, Active.  [PDQ Clinical Trial]

 

History

Mistletoe has been used for centuries for its medicinal properties. Reviewed in [1-6] It was reportedly used by the Druids and the ancient Greeks, and it appears in legend and folklore as a panacea. It has been used in various forms to treat cancer, epilepsy, infertility, menopausal symptoms, nervous tension, asthma, hypertension, headache, and dermatitis. 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 cancer have been published since the early 1960s.[7-36] Reviewed in [3,37,38] Most of the results of these studies were published exclusively in German. (See Human/Clinical Studies section.)

As indicated previously (General Information section), proposed mechanisms of action for mistletoe that are relevant to cancer include stimulation of the immune system [7,39-68] Reviewed in [1-3,8-11,37,38,69-72] and a direct toxic effect on tumor cells.[73-89] 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.[91-94] Reviewed in [95]

Mistletoe has been shown to stimulate increases in the number and the activity of various types of white blood cells.[7,40-68] Reviewed in [2,3,8,9,11,29,38,69-72,93,95-98] 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 [1,3,8,11,29,37,38,69-72,91,93-96,98] Other evidence suggests that mistletoe exerts its cytotoxic effects by interfering with protein synthesis in target cells [4,73,81,90,99] Reviewed in [3,8,61,69-72,79,86,89,92,95,98,100,101] 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]

Although viscotoxins and lectins have both been investigated as active components in mistletoe, most research has focused on the lectins.[4,7,9-11,45,47,48,51-54,56,57,59-62,66,73-76,81-83,86,88-90,95-99,99,101,101] Reviewed in [3,8,12,37,69,70] Purified mistletoe lectins have demonstrated cytotoxic and immune-system-stimulating activities. Four different lectins—ML-I, ML-II, ML-III, and Viscum albumchitin-binding agglutinin—have been identified in mistletoe extracts to date. ML-I (or viscumin) may be responsible for many of mistletoe’s biological effects. When a laboratory method was used to selectively deplete ML-I from Viscum album extracts, their cytotoxic and immune-system-stimulating properties were markedly reduced.[62,83] It should be noted that fermentation eliminates most of the ML-I in mistletoe extracts.[104] Reviewed in [2,100]

ML-I consists of an alpha chain and a beta chain, which can be separated from one another.[4,53,86,89,90] Reviewed in [2,3,8,12,59,61,69-71,79,81,86,88,95,98-101] 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-I alpha chain has been coupled to monoclonal antibodies to produce "immunotoxins" that target and kill specific cell types.[105,106] Reviewed in [70]

More Information about the immune system and how it works.

References

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