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 [37,3,38] 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 [39-62,7,63-68] Reviewed in [69,70,1,8,37,2,71,72,3,9-11,38] 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.[40-62,7,63-68] Reviewed in [69,70,8,2,71,72,3,9,11,29,93,95-98,38] 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 [69,70,1,8,37,71,3,72,11,29,91,93-96,98,38] Other evidence suggests that mistletoe exerts its cytotoxic effects by interfering with protein synthesis in target cells [73,81,90,4,99] Reviewed in [79,86,69,61,8,70-72,3,89,100,92,95,98,101] and by inducing apoptosis.[83,95,102] Reviewed in [87,69,63,72,3,98] 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.[73-76,81-83,86,90,45,47,48,51-54,56,57,59-62,99,7,66,9-11,4,88,89,95-98,101] Reviewed in [69,8,70,37,3,12] Purified mistletoe lectins have demonstrated cytotoxic and immune-system–stimulating activities. Four different lectins—ML-I, ML-II, ML-III, and Viscum album chitin-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.[83,62] 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.[86,90,53,4,89] Reviewed in [79,81,86,59,69,61,70,2,8,71,3,88,99,12,100,95,98,101] 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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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.  [PUBMED Abstract]
    
    
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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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
90. Franz H: Mistletoe lectins and their A and B chains. Oncology 43 (Suppl 1): 23-34, 1986.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
100. Jäggy C, Musielski H, Urech K, et al.: Quantitative determination of lectins in mistletoe preparations. Arzneimittelforschung 45 (8): 905-9, 1995.  [PUBMED Abstract]
     
     
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.  [PUBMED Abstract]
     
     
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.  [PUBMED Abstract]
     
     
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.  [PUBMED Abstract]
     
     
104. Wagner H, Jordan E, Feil B: Studies on the standardization of mistletoe preparations. Oncology 43 (Suppl 1): 16-22, 1986.  [PUBMED Abstract]
     
     
105. Wiedłocha A, Sandvig K, Walzel H, et al.: Internalization and action of an immunotoxin containing mistletoe lectin A-chain. Cancer Res 51 (3): 916-20, 1991.  [PUBMED Abstract]
     
     
106. Tonevitsky AG, Toptygin AYu, Pfuller U, et al.: Immunotoxin with mistletoe lectin I A-chain and ricin A-chain directed against CD5 antigen of human T-lymphocytes; comparison of efficiency and specificity. Int J Immunopharmacol 13 (7): 1037-41, 1991.  [PUBMED Abstract]
     
     

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