mistletoe

I Introduction
Mistletoe is a unique hemiparasitic plant that has extensive historical use as a medicine and also as an ubiquitus religious and poetic symbol. Encompassing reference in the writings of Pliny, Virgil, Norse Mythology, and also Celtic religion, its image as inferred from these sources is one embodying a dichotomy of empowerment and vitality juxtaposed with death and the supernatural. Regarded as a "cure-all" by Celtic religion, its mythological medicinal properties seem only but fictitious, yet modern oncology research and chemical analyses have revealed mistletoe's extremely formidable efficacy in cancer treatment and also extremely unique mechanisms of medicinal action. Given contemporary scientific research, it is interesting and worthy of note that the ancient use of mistletoe inferred via its recorded images and cultural roles might in some ways have rivaled modern medicine. In Pliny's writings and as supported by archaeological evidence, mistletoe has been afforded the role of a "cure-all" and a central element in Druidic practices, and is simultaneously related with ceremonial sacrifice and death. Within Virgil's Aeneid, mistletoe bestows much power and is associated with high value and importance, yet is intricately related to the underworld, death, and supernatural power. Mistletoe's role in Norse mythology goes from being remote and benign to the only thing capable of bringing about the death of a central god.
In modern research mistletoe has exhibited formidable antitumoral, cytotoxic, and immunomodulatory properties efficacious in the treatment of cancer. Isolation of its active constituents has revealed clues with regard to its specific medicinal functionality, yet its holistic mechanisms of action remain ambiguous as of yet due to what seems to be a complex synergy between its constituents. Primary constituents of mistletoe that have been the foci of modern research include: lectins, alkaloids, polysaccharides, and viscotoxins. Isolated lectins, alkaloids and viscotoxins have exhibited some degree of the cytotoxic and immunomodulatory effects associated with bulk extracts, yet bulk extracts seem to be less harmfully toxic and more active at relatively lower concentrations. Iscador, a mistletoe extract used since the 1920's, has been recorded to have antitumoral effects in vitro and immunomodulatory effects in vitro and in vivo. Fermentation of the mistletoe extract alters its medicinal activity to a significant degree and this change is thought to be related to the degradation of the most toxic lectins. It is postulated that the efficacy of mistletoe extracts like Iscador are due to a synergy between both its components that are medicinally active when isolated, and those components like polysaccharides that are medicinally unactive yet can conglomorate with the more active constituents to form complexes. The historic interplay in mistletoe's image between life and death in some ways reflects its physiological properties in being both toxic and capable of drastically improving health.

II Botany
Mistletoe, Viscum Album, is a hemiparastic plant growing on a variety of host trees and shrubs, many species found in the Loranthaceae, Viscaceae, and Eremolepidaceae families. The European population of mistletoe is divided in three subspecies within the Loranthaceae family with regard to the host tree it grows on: Platyspermum (dicotyledonous trees), abietis (growing on Abies species), and laxum (pine and rarely spruce trees). Viscum album Loranthaceae is found from Northern Europe to Northwest Africa, from East Europe through Southwest and Central Asia to Japan. Susceptibility of trees and shrubs to mistletoe parasitism is defined by distinct mechanical and chemical factors. The thicker the phellem (outer part of the bark) and the more superficial fibers the tree has decreases the mechanical susceptibility of the tree. Chemical susceptibility involves a more ambiguous process of polyphenol-secretion stimulated by mistletoe. Mistletoe depends on its respective host for water and mineral nutrition, even though it produces its own carbohydrates via photosynthesis and no organic substances are transported between mistletoe and its host. It transpires at a much higher rate than its respective hosts, where transpiration is higher in mistletoe when host nitrogen content is lower. The type of host tree seems to largely influence the chemical compounds (especially alkaloids) found in the respective mistletoe, and mineral content in mistletoe has been found to be much higher than that in the host, especially relative to the infected branch. Mistletoe is primarily propagated via birds, either through the dispersion of seeds in dung from ingested berries or by birds cleaning their beaks of mistletoe seeds on tree bark. Small insect-pollinated flowers are found opening on mistletoe between the end of February and April, insects being attracted by a fruit-like smell and floral nectar. (1)

III History
In Virgil's Book VI of the Aeneid mistletoe is written of in comparison to the central metaphorical image of the Golden Bough, embodying supernatural, vitally empowering, and death-related elements. "Like mistletoe that in the woods in winter Thrives with yellowish berries and new leaves- A parasite on the trunk it twines around- So bright amid the dark green ilex shone The golden leafage, rustling in light wind. Aeneas at once briskly took hold of it And, though it clung, greedily broke it off, Then carried it to Sibyl's cave." 10 (p. 167)

Awareness of mistletoe's parasitic nature is explicitly evident here, intertwined with allusions to death, the supernatural, and more subtly, to giving of life. Sibly's cave is the entrance to the underworld, entry limited to those who have plucked the golden bough. The golden bough gives Aeneas the ability to further his journey while simultaneously stimulating his consciousness of death. It is ambiguous whether Virgil intended the Golden Bough to be a direct representation of mistletoe, such that he differentiates them in simile for the sake of poetry. Earlier in Book VI the supernatural and empowering parts of the Golden Bough are elaborated, again in dichotomy with death:
"A tree's deep shade conceals a bough whose leaves And pliant twigs are all of gold, a thing Sacred to Juno of the lower world. The whole grove shelters it, and thickest shade In dusky valleys shuts it in. And yet No one may enter hidden depths Below the earth unless he picks this bough, The tree's fruit, with its foliage of gold." 10 (p. 164)

The bough bears golden foliagee described as the "tree's fruit" in contrast to the later passage above in which the parasitic nature of the bough becomes the focus. Gold suggests the implication of high value and the mistletoe as fruit could allude to nutritive or life-giving value. Simultaneously, the plucker of the golden bough is empowered with the ability to gain entrance into the underworld, again linking the golden bough and mistletoe less directly with death and supernatural.

Norse mythology makes reference to mistletoe in the death of the god Balder: "I behold Fate looming for Balder, Woden's son, the bloody victim. There stands the Mistletoe slender and delicate, blooming high above the ground. Out of this shoot, so slender to look on, there shall grow a harmful fateful shaftŠ" (9) (p. 16)

"Loki, who knew the secret of the mistletoe, inveigled blind Hod into casting a dart with amisteltoe warhead at Balder, and the latter fell immediately." (9) (p. 53)

Balder is the son of Odin, the god of all Vikings, and Frigg the Goddess of marriage. Hod is Balder's blind fraternal twin and Loki the mischievous god. Balder had a dream foretelling his death by his brother's hand, after which Frigg attained protection for Balder from all things but mistletoe, excluding it because it was too young. Loki subsequently tricked blind Hod into throwing a dart made of mistletoe at Balder, leading to Balder's death. Thus mistletoe assumes a somewhat sinister role in Norse mythology through association with Loki and as the "harmful fateful shaft" leading to Balder's death.

Celtic religion is thought to have held mistletoe in extreme sanctity and as central to Druidic practices. Pliny the elder writes in Book XVI:

"The Druids‹that is what they call their magicians‹hold nothing more sacred than mistletoe and a tree on which it is growingŠwhen it [mistletoe] is discovered it is gathered with great ceremonyŠHailing the moon in a native word that means Œhealing all things,' they prepare a ritual sacrifice and banquet beneath a tree and bring up two white bulls, whose horns are bound for the first time on this occasion. A priest arrayed in white vestments climbs the tree and with a golden sickle cuts down the mistletoe, which is caught in a white cloak. Then finally they kill the victims, praying to God to render his gift propitious to those whom he has bestowed it. They believe that mistletoe given in drink will impart fertility to any animal that is barren, and that it is an antidote for all poisons." 11 (p. 549)

The validity of Pliny's passage is supported by corroboration with more known elements of Celtic culture. Miranda Green acknowledges mistletoe, feasting, the moon, and bull sacrifice as familiar components of Celtic religion. The mistletoe appears as a motif in early Celtic art; human heads bear leaf-shaped crowns on jewelry and stone monuments. Evidence of ritual banquet is found as representations in Celtic tombs and shrines. The moon is associated with healing Celtic goddesses depicted wearing lunar amulets. Cattle were commonly used by the Celts as sacrificial animals, evidenced by engravings and sacrificial shrines. Additionally, in 1984 a body found in England dating back to the Celtic Iron Age suggests ritualistic use of mistletoe in a Druidic death ceremony. The man was found with mistletoe pollen in his stomach, was naked except for an armlet of fox-fur and body paint, and his cause of death inferred to be a slit-throat. The carbon dating, evidence of ritual, and finding of ingested mistletoe adds possible validity to the integral role of mistletoe in Druidic practices. Pliny's passage, given the support of archaeological findings thus strengthens the common theme associated with mistletoe's history of life-giving nature intertwined with the supernatural and death.

It has become a contemporary holiday custom to kiss under the mistletoe. Numerous explanations exist for this holiday custom, yet mistletoe's modern association with merriment provides interesting contrast with its historical background.

IV Medicinal Use / Contemporary Research
Mistletoe extracts have exhibited both cytotoxic and immunomodulatory properties which have been efficacious in the treatment of cancer. These have been experimentally evaluated in vitro and in vivo. Isolation of lectin and alkaloid compontents of mistletoe extracts have yielded tumor-reducing properties, yet none of these isolated components have been comparable to the effectiveness and relatively low-toxicity of the bulk fermented extract. Constituents of mistletoe with tumor-reducing components include: lectins, viscotoxins, alkaloids, polysaccharides, and polyphenolic substances. Other components include: carbyohydrates, phenolic compounds, sterols, triterpenes, and amines. Factors for testing mistletoe's ability to inhibit the cell-growth of cancerous cells include: type of cell-line, mistletoe species, preparation method (such as fermentation), and the host tree species (due primarily to variable alkaloid content).

The commercial extract Iscador developed in the 1920's has produced the following results in breast cancer patients after one intravenous infusion: enhancement of phagocytic activity of granulocytes (white blood cells); significant increase in natural killer and antibody-dependent cell mediated cytotoxicity; and augmented levels of large granular lymphocytes (white blood cells). The monitored kinetic responses of the immune system with Iscador are similar to those attained after treatment with alpha-ineterferon, which is used to stimulate the immune system in cancer patients. 7 A German study published in 2001 found that Iscador treatment of cancer patients led to prolongation of survival time and stimulation of psychosomatic self-regulation. 15 In vitro studies with Iscador on rat hepatoma tissue culture (HTC) cells and human leukemia Molt 4 cells have yielded cytotoxic effects variable with regard to whether or not a fermented or unfermented extracts were used. Both fermented and unfermented extracts induced rapid lysis of cellular membranes and DNA synthesis inhibition. On Molt 4 cells the fermented extract produces cytolysis after a longer time of action, but the fermented extract is also more potent than unfermented in HTC cell growth inhibition. Unfermented has a stronger cytotoxic effect on Molt 4 than HTC and also has 10 times more lectins. Fermented Iscador was more effective than the well known antitumoral agent 5-fluorouracil (a 5-thymidylate synthase inhibitor) in these tests. 5 The variability due to the fermentation processes is most likely due to the breaking down of toxic lectins.

Three different mistletoe lectins (ML) have been currently isolated. Lectins are proteins or glycoproteins with specific binding sites for sugars which are not antibodies or enzymes. MLI has shown specificity for D-galactose, seems to be the most toxic of the three, and is degraded in fermentation. It is a two-chain conjugate of enzyme and lectin. MLII is D-galactose and N-acetyl D-galactosamine specific. MLIII is N-acetyl D-galactosamine specific. The lectins react with erythrocytes (red blood cells) and immunoglobulins (antibodies) and have experimentally induced cytotoxicity by inhibiting protein synthesis on the ribosomal level. A-chain properties: mitogenicity and inhibition of synthesis in cell-free systems; candidate for construction of immuotoxins. B-chain properties: activate macrophages and release lymphokines from lymphocytes; inhibit allergen-induced histamine release from leukocytes and collagen-induced serotonin release from platelets. Purified lectins produced similar effects to unfermented Iscador extract on both HTC and Molt 4 cells, yet HTC cells are 100 times less sensitive to this than Molt 4 cells. 3,7

Viscotoxins, or thionins, are cytotoxic small molecular weight proteins that inhibit cell growth in vitro at concentrations 100-fold higher than inhibitory lectin concentrations. 8 They have been shown to exhibit stimulatory and cytotoxic effects on immune cells 17, and in a more specific study it was found they exert a strong immunomodulatory effect on human granulocytes (white blood cell type) 20. It has also been postulated that they might be acetylcholine agonists 16.

Polysaccharides in mistletoe play a more ambiguous role as of yet in contrast to the more directly active constituents; they seem function more in association with the lectins and other mistletoe components. In mistletoe berries the sugar complex arabinogalactan is the predominant polysaccharide while in green parts highly esterified galacturonan is more abundant. Although in immunological tests the isolated polysaccharides failed to increase phagocytic activity of granulocytes and macrophages, there is specifc evidence that there are significant interactions between arabinogalactan and galactose-specific lecin (MLI). Therefore, even though mistletoe polysaccharides may not exhibit significant medicinal properties, a synergy may exist between them and other constituents of mistletoe to produce the extract's medicinal effects. 2 Studies on interactions between lectins and polysaccharides found in mistletoe show that agglutination of immune cells by lectins is increased with the presence of mistletoe polysaccharides 18.

Alkaloids are structurally unrelated, basic nitrogenous compounds that possibly act as a plant defense mechanism against animal and parasitic infection. The alkaloids isolated from California, European, and Korean mistletoe have shown variable degrees of activity, with Korean highest in activity. Isolated alkaloids from Korean mistletoe have produced antitumor effects at relatively high doses with low toxicity and may play contribute to extract cytotoxicity. Alkaloids may exist as glycoconjugates with lectins and/or viscotoxins. It is thought that mistletoe alkaloids are sequestered by the parasite from the host tree. 5

Although the exact nature of mistletoe's historic use cannot be inferred, its centrality in the Aeneid, integral role in Celtic culture, and unique importance in Norse mythology all incur questioning why mistletoe assumed such prominence. Its unique botany no doubt provoked interest in poetic metaphor, yet its Celtic reputation for being a "cure all" contrasted with modern research in mistletoe's bioactivity suggests ancient knowledge of its medicinal properties and its medicinal use to be far more credible and deep than merely primitive or mythological fiction.

V Bibliography
1. H. Becker: "Botany of European Mistletoe (Viscum album L.)" Oncology 43: suppl. 1, pp. 2-7 (1986)
2. E. Jordan, H. Wagner: "Structure and Properties of Polysaccharides from Viscum album (L.)" Oncology 43: suppl. 1, pp. 8-15 (1986)
3. H. Wagner, E. Jordan, B. Feil: "Studies on the Standardization of Mistletoe Preparations" Oncology 43: suppl. 1, pp. 16-22 (1986)
4. Hartmut Franz: "Mistletoe Lectins and Their A and B Chains" Oncology 43: suppl. 1, pp. 23-24 (1986)
5. Gilles Ribereau-Gayon, Marie-Louise Jung, Dominique Di Scala, Jean-Paul Beck: "Comparison of the Effects of Fermented and Unfermented Mistletoe Preparations on Cultured Tumor Cells" Oncology 43: suppl. 1, pp. 35-41 (1986)
6. Tasneen A. Khwaja, Cecilia B. Dias, Stephanie Pentecose: "Recent Studies on the Anticancer Activities of Mistletoe (Viscum album) and Its Alkaloids" Oncology 43: suppl. 1, pp. 42-50 (1986)
7. Hajto, Tibor: "Immunomodulatory Effects of Iscador: A Viscum album Preparation" Oncology 43: suppl. 1, pp. 51-65 (1986)
8. Hajto, Tibor; Oncology 50: pp. 393-398 (1993)
9. Thompson, Lawrence S.: Norse mythology; the Elder Edda in prose translation, 1974.
10. Virgil's Aeneid; translated by Robert Fitzgerald; Vintage Books, 1984
11. Pliny the elder: Natural History; Book XVI
12. Green, Miranda J.: "The World of the Druids" Thames and Hudson, London (1997).
13. http://www.ugcs.caltech.edu/~cherryne/myth.cgi/Introduction.html
14. http://cancernet.nci.nih.gov/cam/mistletoe.htm
15. Grossarth-Maticek R. Kiene H. Baumgartner SM. Ziegler R: "Use of Iscador, an extract of European mistletoe (Viscum album), in cancer treatment"; Alternative Therapies in Health & Medicine. 7(3):57-66, 68-72, 74-6 passim, 2001 May-Jun.
16. Anderson, LA; Phillipson, JD; "Mistletoe‹the Magic Herb"; Pharmaceutical Journal 229: 437-439
17. Stein GM, Schaller G, Pfuller U, Wagner M, Wagner B, Schietzel M, and Bussing A: "Characterisation of granulocyte stimulation by thionins from European mistletoe and from wheat"; Biochimica et Biophysica Acta. 1426(1):80-90, 1999 Jan 4.
18. Edlund U, Hensel A, Frose D, Pfuller U, Scheffler A: "Polysaccharides from fresh Viscum album L. berry extract and their interaction with Viscum album agglutinin I."
19. Romagnoli S. Ugolini R. Fogolari F. Schaller G. Urech K. Giannattasio M. Ragona L. Molinari H.: "NMR structural determination of viscotoxin A3 from Viscum album L."; Biochemical Journal. 350 Pt 2:569-77, 2000 Sep 1.
20. Stein GM. Schaller G. Pfuller U. Schietzel M. Bussing A.: "Thionins from Viscum album L: influence of the viscotoxins on the activation of granulocytes"; Anticancer Research. 19(2A):1037-42, 1999 Mar-Apr.