Mistletoe Extracts from the Anthroposophical Point of View

images  15 Mistletoe Extracts from the Anthroposophical Point of View


Arndt Büssing


images   Introduction


Treatment of cancer patients with extracts from Viscum album L., the white-berried European mistletoe, is one of the most widely used forms of complementary cancer therapy in Europe. Many scientists have pointed out the obvious discrepancy between the popularity of mistletoe extracts in cancer treatment and its classification, by conventional medicine, as a treatment modality of unproved efficacy. Reservations about this form of adjuvant cancer therapy still exist.


Mistletoe extracts have been used in the treatment of cancer patients since the beginning of the twentieth century. Their introduction in cancer therapy by the philosopher Rudolf Steiner was not based on an empirical acquisition of knowledge through experiments, as is standard procedure today, but on ideas in the field of Humanities (13). The therapeutical principles of mistletoe uses in Anthroposophical Medicine are described in detail by Fintelmann (for a review, see ref. 13). Upon Steiner’s suggestion, injectable mistletoe preparations were developed for the treatment of cancer patients, and these have been used exclusively by anthroposophical physicians. Meanwhile, mistletoe therapy has stepped out of the sphere of anthroposophy and has also been used by physicians who see themselves as belonging to a more conventionally oriented medicine. In Germany, the approval of mistletoe extracts for treating cancer patients is based on the monographs of Commission C (Anthroposophic Medicine) and Commission E (Phytotherapy) of the former Federal Health Department.


images   Mistletoe Extracts


Unlike manufacturers of phytotherapeutic mistletoe extracts, the pharmaceutical companies claiming to produce mistletoe extracts according to Steiner’s suggestions use juices from mistletoe harvested in both summer and winter. These juices are then mixed by using a special whirling process. From the anthroposophical point of view, it is this special process that creates the effective medication.


The fresh leaves, short branches, and mistletoe berries—and sometimes the layer (rooting shoot)—are used for producing the extracts (Table 15.1). Depending on the manufacturer, the mistletoe plant is either subjected to fermentation, pressed, or extracted with cold water (8).


Pharmaceutical manufacturers with an anthroposophical orientation offer mistletoe preparations derived from different host trees. Mistletoe from apple trees is primarily used for treating women with mammary carcinoma, while mistletoe from oak or pine trees is used more frequently for tumors in men. This peculiarity also goes back to recommendations by Steiner, who assigned mistletoe plants derived from certain host trees to certain organ systems. There is still no definite evidence of a tumor-specific effect of mistletoe from certain host trees. One cannot suggest that the application of mistletoe extract from a defined host tree should be recommended for the treatment of a particular type of cancer. Nevertheless, when choosing a preparation for the patient, it may be of advantage to know that mistletoes derived from different host trees are believed to have different potencies.


In anthroposophical medicine, only the specially mixed mistletoe juice, rather than a single defined ingredient, is regarded as effective medication. Nevertheless, clinically relevant reactions can still be assigned to certain constituents (Fig.15.1).


In the 1990s, the main interest of scientific research on mistletoe (to which anthroposophical medicine is not explicitly in opposition) was directed toward mistletoe lectins. These proteins have reproducible pharmacological activities even in nanogram concentrations, whereas other substances require distinctly higher concentrations.


Currently, the most important effects that have been confirmed experimentally are:


image


Fig. 15.1 Overview of the immunomodulating effects of defined Viscum album constituents.


– induction of programmed cell death (apoptosis)


– modulation of the immune response


– protection of DNA against chemotherapeutic agents (8, 9).


The cytotoxic effects of mistletoe extracts can be assigned to mistletoe lectins as well as viscotoxins, while the immunomodulating effects are not restricted to mistletoe lectins but are also induced by polysaccharides and oligosaccharides, and viscotoxins (Fig. 15.1).


images   Experimental Studies


After administering mistletoe extract to cancer patients by injection, a circumscribed reddening of the skin may occur at the injection site, and this may be accompanied by a rise in body temperature. If one imagines the tumor as “condensed cold,” this “cold” can then be “dispersed” by the “heat” of the mistletoe. The patient is thus motivated to tackle the tumor as well as his/her surroundings; the patient is stimulated to become more active again, to “warm” to his/her social milieu. According to Steiner, the tumor can only disperse if one succeeds in “wrapping the growth into a warm coat,” i. e., if the mistletoe injection produces fever. The local reaction and febrile condition are immunological reactions to the injection of “foreign” material to which the body must respond. The “warm coat” can be compared with peritumoral (inflammatory) infiltration: the immunocompetent cells begin to attack the tumor cells.


To explain the therapeutic approach of using mistletoe extract, at least three hypotheses are being discussed that can be tested in scientific studies: cytotoxicity, immunomodulation, and enhancing the quality of the patient’s life. They are discussed in detail in the following sections.


Cytotoxicity


Generally speaking, there is a higher tendency toward cell proliferation within the tumor than in the normal tissue; the tumor cells have become largely independent from the death signals that limit the growth of cells. Mistletoe extracts induce apoptotic cell death in tumor cells as well as nonmalignant cells (8, 9). The apoptosis-inducing potentials of mistletoe extracts derived from different host trees correlate closely with the contents of cytotoxic mistletoe lectins, while necrotic cell death is rather caused by viscotoxins—as becomes evident when using very high concentrations of viscotoxins.


Table 15.1 Affected lymphocyte populations (2)













Mistletoe lectin I   Eliminates primarily CD16+/CD56+ CD8NK cells
Mistletoe lectin III   Eliminates primarily CD8+ lymphocytes (phenotype of suppressor/memory CD8+ CD28+ CD62Llo T cells)
Less sensitive to mistletoe lectin III   CD8+ CD28+ CD62Lhi naïve/cytotoxic T cells
  CD4+ T helper/inducer lymphocytes
  CD19+ B cells

Mistletoe Lectins


Mistletoe lectins are ribosome-inactivating proteins that differ from each other with regard to sugar specificity and molecular weight (50–63 kDa). Mistletoe lectin I binds to D-galactose, while mistletoe lectin II and mistletoe lectin III bind to N-acetylgalactosamine (8, 9).


Mistletoe lectins cause inhibition of protein biosynthesis in cell-free systems and apoptosis in cultured cells. A few minutes after incubating human lymphocytes with mistletoe lectins, there is an increase in intracellular Ca2+, which is regarded as expression of a “receptor-mediated signal.” A few hours later, membrane changes (blebbing) and chromatin condensation with the following after-effects can be observed (2, 3, 5, 8, 9):


– production of mitochondrial oxygen intermediary products


– expression of mitochondrial Apo-2.7 molecules


– mitochondrial release of cytochrome c


– caspase activation with subsequent degradation of various proteins and kinases


– translocation of phosphatidylserine from the inner to the outer layer of the mitochondrial membrane


– fragmentation of DNA.


Conventional “death receptors” such as Apo-1/Fas (CD95) or TNF receptor type 1—which are of special importance for apoptotic signaling and caspase activation—do not seem to be directly stimulated by mistletoe lectins (8, 9).


In patients with metastasizing tumors (and also in HIV patients), suppressor/memory T cells predominate, while cytotoxic T lymphocytes are underrepresented. Hence, a possible therapeutic approach could be the elimination of these cells in favor of cytotoxic T lymphocytes by treatment with ML-III (Table 15.2). It should be investigated whether this selective effect can be utilized in clinical applications.


Incubation of human lymphocytes with mistletoe lectins caused a significant up-regulation of CD95L surface molecules in the surviving lymphocytes (6). This Fas ligand induces apoptosis in Fas+ target cells; hence, the tumor cells should also be attacked by stimulated Fas ligand-positive lymphocytes, in addition to direct mistletoe lectin-induced cell death. It should be clarified how the subcutaneous injection of a mistletoe preparation can yield a “distant” effect by means of activated lymphocytes, although these do not seem to proliferate.


Viscotoxins


  Viscotoxins belong to the family of α-thionines and β-thionines, a group of alkaline cysteine-rich polypeptides with a molecular weight of 5 kDa. The toxicity of viscotoxins has been determined primarily in animal experiments. In cats, intravenous administration of viscotoxins at a final concentration of 0.1 mg/kg body weight resulted in the death of all animals, while the LD50 in mice was 0.5 mg/kg body weight (27). Application of viscotoxins at low concentrations caused a drop in blood pressure, bradycardia, and negative inotropy of the heart.


  Incubation of human lymphocytes or Molt-4 leukemia cells with viscotoxins caused rapid permeabilization of the cell membrane, swelling of mitochondria associated with a loss of their cristae, and the formation of oxygen metabolites within a few minutes or hours (35). This indicated accidental (necrotic) cell death. Unlike in granulocytes, it seemed as if the formation of reactive oxygen metabolites in lymphocytes and tumor cells was no longer compensated by the cellular redox systems (such as glutathione) (4).


  Viscotoxins thus induce necrotic cell death, which leads to rupture of the cell membrane and release of cell organelles into the intercellular space and, therefore, causes inflammatory tissue reactions. By contrast, mistletoe lectins cause apoptotic cell death, which causes condensation of the cell into apoptotic bodies that are phagocytosed by the neighboring cells without inducing inflammatory tissue reactions.


  According to the above-mentioned working model, viscotoxins cause a “dispersing reaction” (or “heat”), while mistletoe lectins cause a “condensing reaction” (or “cold”)—which is the physiological state of the body.


  The direct cytotoxic effect of mistletoe extracts can be demonstrated in an impressive way in cell cultures and animal experiments (9, 18). In a clinical setting, however, subcutaneous and intravenous administration hardly yields such an effect. This might be due to the induction of anti-ML antibodies during mistletoe therapy (9, 18), but—even before the formation of antibodies—also to inhibition of mistletoe lectin activity by serum glycoproteins and lipids (25, 26).


  In animal experiments, a clear inhibition of growth and/or prolonged survival times can be achieved by injection of mistletoe extracts in case of the following tumors (9):


– B16F10 melanoma

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Jun 13, 2016 | Posted by in ONCOLOGY | Comments Off on Mistletoe Extracts from the Anthroposophical Point of View

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