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Mistletoe (Viscum album)


Mistletoe (Viscum album) Image
Synonyms / Common Names / Related Terms
ABNOBAviscum®, Abnovaviscum Quercus (AQ), all-heal, American mistletoe, Australian mistletoe, avuscumine, bird's lime, birdlime mistletoe, devil's fuge, Drudenfuss, Eurixor®, European mistletoe folia visci, galactoside-specific lectin, golden bough, Helixor®, Herbe de qui (French), Hexenbesen, Iscador® QuFrF, Iscador Qu spezial, Isorel®, Leimmistel, Lektinol®, Lignum crusis (Latin), Loranthaceae (family), Mistlekraut (German), Mistelsenker, Mistletein, mistletoe extract PS76A2, mistletoe lectin (ML), mistletoe of the appletree (Malus), mistletoe of the fir (Abies), mistletoe of the pine (Pinus), mistrel, ML-1, mystyldene, Phoradendron flavescens (Pursh.) Nuttal, Phoradendron leucarpum, Phoradendron macrophyllum, Phoradendron serotinum (Raf.), Phoradendron tomentosum (DC) (American mistletoe), Plenosol®, Stripites Visci, Tallo de muerdago, VaQuFrF, Vischio (Italian), Visci, Visci albi folia, Visci albi fructus, Visci albi herba, Visci albi stipites, viscum, Viscum abietis, Viscum album coloratum (Korean mistletoe), Viscus album quercus frischsaft [Qu FrF], Viscum austriacum, Viscum fraxini-2, viscumin, Vogelmistel, Vysorel®, white mistletoe.

Mechanism of Action

Pharmacology:

  • Constituents: Plant proteins with high affinity to specific cellular glycoconjugates: Lectin I (D-galactose-and N-acetyl-D-galactosamine, and sialoglycoproteins specific lectin)37,38,39,40,41, Lectin II and III (N-acetyl-D-galactosamine specific proteins)9. Crude mistletoe extract contains three lectins with different molecular weight and specificity.42 These three lectins agglutinate human erythrocytes and react with immunoglobulins. The mistletoe lectin I is a naturally occurring conjugate of a lectin (B chain) and of an enzyme (A chain).43 The cytotoxicity observed with mistletoe lectin I is caused by inhibiting the protein synthesis on the ribosomal level. Prominent properties of the A chain are mitogenicity and inhibition of the protein synthesis in cell-free system. The B chain activates macrophages and release lymphokines from lymphocytes. The contents and proportions of the isoforms in the mistletoe vary with host tree and harvest time of the year.44,45,45 Mistletoe also contains viscalbCBA, chitin binding protein, and viscotoxins (A1-3; B), which are toxic proteins related to the family of thionins, highly basic cysteine-rich polypeptides. The content and proportions of the isoforms are quite constant in mistletoe from various trees and harvest time of the year.3,30 The green parts of mistletoe contain highly esterified D-galacturonan. However, in mistletoe berries, a complex arabinogalactan is present3, as well as phenylpropanoids: syringin, syringenin-apiosylglucoside46,2, Eleutheroside E2, flavanone glycosides, and alkaloids47.
  • Antineoplasm/antiproliferative properties: Extensive literature exists on the use of mistletoe in cancer treatment. In vitro (cell-free and cellular preparations) and animal studies have shown Viscumin (lectin-1 or ML-1) to be cytotoxic to 3T3 cells, lethal to mice, and a potent inhibitor of protein synthesis.17,18,19,20,21,22,23,24,25 The lectins may target the carbohydrates on the cells' surface causing agglutinations.26,27,28,29,30,6,10 Lectins can induce apoptosis in lymphocytes (activity: ML-3>ML-2>ML-1), human peripheral blood lymphocytes, human peripheral blood monocytes, murine thymocytes, human monocytic THP-1 cells, and human K 562 tumor cells, and in animal studies31,32,33,34,35, as well as an increase in the activity of natural killer cells and granulocyte phagocytosis in patients with breast cancer; however, in experimental urothelial carcinogenesis in rats, there is a lack of evidence for a modification or inhibitory effect of the immunomodulatory galactoside-specific mistletoe lectin ML-148. Several mechanisms have been proposed (i.e., ML-1 apoptosis of leukemic B- and T-cell line via caspase-8; ML-2 activates c-Jun N-terminal kinase 1) in apoptotic death of U-937 cells. It has not been established whether apoptosis is a primary or secondary event to inhibition of ribosomal protein synthesis.49,45,50,51,52,53 Purified lectins- ML-I (D-galactose specific), ML-II and III (N-acetyl-D-galactosamine-specific) proteins demonstrated cytotoxicity in killing cells, which was mediated by induction of apoptosis as measured by appearance of hypodiploid nuclei (DNA peak) in flow cytometery. Cytotoxicity may also occur as a result of lectins damaging cell membranes with an influx of Ca2+ and cell shrinkage.5 In tumor patients, regular subcutaneous injections of the optimal dose of mistletoe lectin-1 (1mg/kg of body weight, twice a week) yielded statistically significant increases in certain acute phase reactants (C-reactive protein, haptoglobin, ceruloplasmin, C3-complement, albumin, and immunoglobulin IgM) after four weeks of therapy54, eliciting a humoral immune response. IgG, but not IgM antibodies, were detected against lectins and other components.55 Injection of mistletoe extract to eight cancer patients caused changes in the levels of TNF-α IL-1, IL-6.56 Induction of increased beta-endorphin plasma levels, which correlated with enhanced activities of blood natural killer- and T-cells (correlation between immune and neuroendocrine systems) has been noted with ML-1.57,58
  • Rhamnogalacturan: Rhamnogalacturan from mistletoe enhanced cytotoxicity of natural killer cells to K-562 cancer cells.59
  • Viscotoxins: Granulocyte phagocytosis was stimulated by viscotoxins.60,61,62,63 Viscotoxins have been shown to result in the generation of reactive oxygen intermediates in human lymphocytes, as well as cell death.45
  • Antiviral activity: Five patients with chronic hepatitis C (HCV) received Iscador for one year with a 6-20% decrease in viral load and normalization of liver inflammation (two patients) without side effects.16 Two other patients were also in complete remission of their elevated AST and ALT.
  • Cardiovascular effects: In European folk medicine, mistletoe was used for cardiovascular disease treatment. The viscotoxins produced reflex bradycardia, negative inotropic effects and vasoconstriction in cardiac muscle of cats, reduced isometric twitch, and produced contracture and progressive depolarization in rabbit heart preparations, a process reversed by calcium.64,65 Phenylpropanoids were proposed to play a role by inhibiting cAMP phosphodiesterase, although the data is currently inconclusive.46,66,2 A study conducted on cats showed that the effect of mistletoe viscotoxin and phoratoxin on blood circulation resulted in reflex bradycardia, negative inotropic effects on the heart, and in high doses vasoconstriction of vessels in skin and skeletal muscle.65
  • Endocrine effects: Aqueous extract of mistletoe (1-10mg/mL) evoked a stepwise (1.1-12.2 fold) stimulation of insulin secretion from clonal pancreatic ß-cells.15 The presence of these insulin-releasing natural products in mistletoe may contribute to the reported antidiabetic property of the plant.
  • Immunologic effects: Subcutaneous mistletoe extract (ABNOBAviscum Mali, AM) therapy caused a strong proliferation of peripheral blood mononuclear cells (PBMC) in breast cancer patients. During the observation period, this initial proliferation decreased in all patients.67 TNF-alpha or IL-6 was found in all of monocyte-/macrophage cells. IFN-gamma and IL-4 were released in vitro. Furthermore, a shift to Th1- related cytokines could be observed. It was suggested that these changes might favorably influence the tumor growth. Iscador QuFrF and Iscador Qu Special show immunomodulating qualities in HIV-positive patients, healthy non-smokers and cancer patients. Iscador QuS seems to activate the cytotoxic CD8-positive lymphocytes, important in cancer patients.68Clinical application of extracts of Viscum album (Plenosol®) and Echinacea purpurea (Echinacin) can produce a stimulation of cell-mediated immunity (one therapeutic administration followed by a free interval of one week), or can have a depressive action (daily administrations of higher doses). These observations were confirmed by lymphokine production and assay, 3H-thymidine incorporation and a skin test with recall antigens (Multitest Merieux).69 Mistletoe treatment may express significant reduction in defined lymphocyte subset and hence, a possibility of immunosuppression.1 Iscador for altered various immune indices, including lymphocyte subsets, natural killer cell activity, phagocytic and oxidative activities of PMN leukocytes, eosinophilia, and acute phase marker haptoglobin7,8,36,4,56,14,70, whereas Iscador Pini [IP] mistletoe preparation was not shown to induce eosinophilia in healthy individuals, and this may be related to its content of mistletoe lectins. In contrast, exposure to the viscotoxin-enriched extract IP did not result in specific changes of hematologic parameters. After injections of nontoxic doses of purified mistletoe lectin-1 or its carbohydrate-binding subunit, significant increases in parameters of the cellular host defense system, such as natural killer cytotoxicity or large granular lymphocyte frequency were noted.71 General immunological activity has also been noted by others.72,13,73,74,75,76,77,78

Pharmacodynamics/Kinetics:

  • A 2004 Phase I trial studied a twice-weekly, one-hour intravenous infusion, of aviscumine (recombinant mistletoe lectin from Viscum album L.); it was observed to have a half-life (T1/2) of 13 minutes. Plasma levels >2ng/mL (mean IC70 of aviscumine in cell lines) were achieved for only 2.3-7.5 hours per infusion. At dose levels >3200ng/kg the Cmax an area under the concentration time curve (AUC) increased in linear fashion with increasing dosages of the drug.11
  • A similar study by the same author studied a once-weekly, 24-hour intravenous infusion of aviscumine. The total half-life (T1/2) was calculated as 2.81 hours. The area under the curve (AUC 0-inf) was 19 h*ng/mL (median) for six evaluable patients at the 5mcg/kg dose.12

References

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