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Mistletoe Extracts (PDQ®)

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Laboratory/Animal/Preclinical Studies

The immune-system -stimulating and cytotoxic properties of mistletoe have been investigated in laboratory and animal studies.

Viscotoxins and lectins have been investigated as active components in mistletoe; most research has focused on the lectins.[1-9] Purified mistletoe lectins have demonstrated cytotoxic and immune-system-stimulating activities. To date, four different lectins: ML-1, ML-2, ML-3, and Viscum album chitin -binding agglutinin have been identified in mistletoe extracts. ML-1 (or viscumin) may be responsible for many of mistletoe’s biological effects. When a laboratory method was used to selectively deplete ML-1 from Viscum album extracts, their cytotoxic and immune-system-stimulating properties were markedly reduced.[10,11] It should be noted that fermentation eliminates most of the ML-1 in mistletoe extracts.[12-14] Polysaccharide and oligosaccharide components of mistletoe extracts with substantial immune-stimulating properties have been reviewed.[15,16]

The molecular structure of ML-1 consists of an alpha chain and a beta chain, which can be separated from one another.[1,1,6-9,13,17,18] 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-1 alpha chain has been coupled to monoclonal antibodies to produce immunotoxins that target and kill specific cell types.[19-21]

Recombinant ML-1, rML (also known as rViscunim or aviscumin) appears to have the same efficacy as plant-based ML-1 in laboratory studies.[22] Since this is not an extract of mistletoe, it is out of the purview of this summary.

The beta chain of ML-1 is responsible for binding to the surface of a target cell.[23] Studies of mistletoe lectin binding to cancer cells have examined whether the extent of cell binding can predict disease outcome or survival. Studies show that the prognostic value of ML-1 binding depends on the type of cancer.[24] For human breast cancer cells, the amount of lectin-bound cells correlates positively with disease outcome. However, for human adenocarcinoma of the lung, there is no correlation between the amount of lectin-bound cells and disease survival.[25] Though much research has looked at this particular aspect, there have not been studies that directly link the concentration of that component to any clinical activity of mistletoe.

Laboratory studies have shown that mistletoe extracts can stimulate the activity of white blood cells in vitro and cause them to release molecules thought to be important for anticancer immune responses. [4,6,8,9,17,26-33] In addition, mistletoe extracts have demonstrated cytotoxic activity against a variety of mouse, rat, and human cancer cells in vitro.[1,8,23,34-37]

There are conflicting reports concerning the stimulation of cancer cell growth in vitro. In one study, the in vitro growth of several types of human cancer cells was stimulated by treatment with low doses of the purified lectin ML-1.[1] However, various other studies found that ML-1 and mistletoe extracts did not induce cell proliferation.[38,39]

A 2004 in vitro study of IscadorQ, a fermented aqueous extract from European mistletoe grown on oaks, against various cell lines demonstrated that sensitivity to this extract varies greatly among cell lines. In sensitive cell lines, a strong effect was seen in epidermal (HaCaT), lung adenocarcinoma (NCI-H125), and breast adenocarcinoma (MCF-7) cell lines whereas, little or no effect was seen in lung squamous cell carcinoma (MR65) and colon carcinoma (Cac0-2, HT-29). Some cells lines were responsive to high or low concentrations of IscadorQ. IscadorQ showed early cell cycle inhibition followed by apoptosis in a dose-dependent manner.[40]

Studies of the ability of mistletoe to inhibit cancer cell growth in animals have yielded mixed and inconsistent results.[5-9,36,41-49] In most of these studies, mistletoe extracts were administered either by subcutaneous injection or by intraperitoneal injection.

In one animal study, treatment with IscadorM increased the survival time of mice that had been implanted with Ehrlich ascites mouse cancer cells, but not L1210 leukemia or B16 melanoma cancer cells.[50] The effect of IscadorM on the growth of tumors formed in mice by three additional types of mouse cancer cells (i.e., Lewis lung carcinoma, colon adenocarcinoma 38, and C3H mammary adenocarcinoma) was also assessed in this study. Treatment with IscadorM substantially reduced the growth rate of all three types of tumors.

In another animal study, mice were administered IscadorM before, during, or after injection with either of two types of mouse cancer cells (i.e., Dalton lymphoma or Ehrlich ascites).[51] In this study, all groups of mice treated with mistletoe showed substantially slower tumor growth than the control groups.

No antitumor effect or improvement in survival was observed when IscadorM was used to treat rats bearing chemically induced mammary carcinomas or tumors formed from rat Walker 256 carcinosarcoma cells.[52] In this study, IscadorM was also not effective in treating mice that had been injected with Ehrlich ascites cells. In addition, IscadorP was found ineffective in treating rats with tumors formed from rat L5222 leukemia cells.

In another study, intratumoral injections of mistletoe extract (abnobaVISCUM Fraxini-2) demonstrated more antitumor activity than intravenous gemcitabine when injected into mouse xenografts of human pancreatic cancer.[53]

Treatment with the mistletoe extract Lektinol (also sold as Plenosol; refer to the General Information section of this summary for more information) has likewise yielded mixed results in animal experiments.[7] Treatment with Lektinol slowed the growth of tumors formed in mice from implants of three types of mouse cancer (i.e., colon adenocarcinoma 38, Renca renal cell carcinoma, and F9 testicular carcinoma) but not in two other mouse cancers (i.e., B16 melanoma and Lewis lung carcinoma).

The anticancer effects of Isorel (also sold as Vysorel; refer to the General Information section of this summary for more information) have been examined in at least two animal studies.[36,54] In one study, IsorelM was used alone or in combination with local x-ray therapy in mice bearing mouse CMC-2 fibrosarcoma tumors.[54] When IsorelM was used alone, no effect on either tumor growth or animal survival was observed. When IsorelM injections were combined with local x-ray therapy of tumors, substantial improvements in survival were found in comparison with the survival of mice treated with local x-ray therapy alone. With local x-ray therapy alone, 22% of mice were cured of their tumors. When local x-ray therapy was combined with IsorelM injections, administered before or after the x-ray treatment, the cure rate increased to 43%. When IsorelM was administered both before and after local x-ray therapy, the proportion of cured mice increased to 67%.

In another study, IsorelM showed antitumor and antimetastatic effects in mice that had been injected with mouse mammary carcinoma cells.[36] The antitumor effects appeared most pronounced when IsorelM was injected in the vicinity of tumors.

The ability of purified or recombinant lectin ML-1 to inhibit the formation of chemically induced bladder tumors in rats has been evaluated in three studies.[5,8,48,55] In two of the studies, purified ML-1 was administered by subcutaneous injection.[5,8,55] Treatment with ML-1 did not reduce the frequency of bladder tumor formation or increase immune system activity in the bladder wall in either study. In the third study, recombinant ML-1 was introduced directly into the bladder through a process known as intravesical instillation.[8,48] In this study, the frequency of bladder tumor formation was reduced by approximately 50% in ML-1-treated animals. As in the other two studies, immune system activity in the bladder wall was not increased substantially. It was concluded that the antitumor effect observed in this study was the result of direct cytotoxic action by the recombinant lectin against malignant cells.[48]

A few animal studies have suggested that mistletoe is beneficial in decreasing the side effects of conventional anticancer therapy (e.g., chemotherapy and radiation therapy) and that it counteracts the effects of drugs used to suppress the immune system.[56-59] In one study, IscadorM was shown to increase the number of white blood cells in mice treated with cyclophosphamide chemotherapy or radiation therapy and to decrease the amount of weight loss due to radiation, but not during cyclophosphamide treatment.[58] In another study, IscadorM was shown to accelerate the recovery of hematopoietic tissue in the bone marrow and spleens of irradiated rats and mice.[56] In another study, the mistletoe product Eurixor was shown to counteract the immunosuppressive effects of treatment with the drug cortisone.[57]

References
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  25. Blonski K, Schumacher U, Burkholder I, et al.: Binding of recombinant mistletoe lectin (aviscumine) to resected human adenocarcinoma of the lung. Anticancer Res 25 (5): 3303-7, 2005 Sep-Oct.  [PUBMED Abstract]

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  40. Harmsma M, Grommé M, Ummelen M, et al.: Differential effects of Viscum album extract IscadorQu on cell cycle progression and apoptosis in cancer cells. Int J Oncol 25 (6): 1521-9, 2004.  [PUBMED Abstract]

  41. Cebović T, Spasić S, Popović M: Cytotoxic effects of the Viscum album L. extract on Ehrlich tumour cells in vivo. Phytother Res 22 (8): 1097-103, 2008.  [PUBMED Abstract]

  42. Seifert G, Jesse P, Laengler A, et al.: Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro. Cancer Lett 264 (2): 218-28, 2008.  [PUBMED Abstract]

  43. Thies A, Dautel P, Meyer A, et al.: Low-dose mistletoe lectin-I reduces melanoma growth and spread in a scid mouse xenograft model. Br J Cancer 98 (1): 106-12, 2008.  [PUBMED Abstract]

  44. Van Huyen JP, Delignat S, Bayry J, et al.: Interleukin-12 is associated with the in vivo anti-tumor effect of mistletoe extracts in B16 mouse melanoma. Cancer Lett 243 (1): 32-7, 2006.  [PUBMED Abstract]

  45. Beuth J, Ko HL, Schneider H, et al.: Intratumoral application of standardized mistletoe extracts down regulates tumor weight via decreased cell proliferation, increased apoptosis and necrosis in a murine model. Anticancer Res 26 (6B): 4451-6, 2006 Nov-Dec.  [PUBMED Abstract]

  46. Braun JM, Ko HL, Schierholz JM, et al.: Standardized mistletoe extract augments immune response and down-regulates local and metastatic tumor growth in murine models. Anticancer Res 22 (6C): 4187-90, 2002 Nov-Dec.  [PUBMED Abstract]

  47. Pryme IF, Bardocz S, Pusztai A, et al.: Dietary mistletoe lectin supplementation and reduced growth of a murine non-Hodgkin lymphoma. Histol Histopathol 17 (1): 261-71, 2002.  [PUBMED Abstract]

  48. Elsässer-Beile U, Ruhnau T, Freudenberg N, et al.: Antitumoral effect of recombinant mistletoe lectin on chemically induced urinary bladder carcinogenesis in a rat model. Cancer 91 (5): 998-1004, 2001.  [PUBMED Abstract]

  49. 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]

  50. 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]

  51. 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]

  52. Berger M, Schmähl D: Studies on the tumor-inhibiting efficacy of Iscador in experimental animal tumors. J Cancer Res Clin Oncol 105 (3): 262-5, 1983.  [PUBMED Abstract]

  53. Rostock M, Huber R, Greiner T, et al.: Anticancer activity of a lectin-rich mistletoe extract injected intratumorally into human pancreatic cancer xenografts. Anticancer Res 25 (3B): 1969-75, 2005 May-Jun.  [PUBMED Abstract]

  54. 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]

  55. 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]

  56. 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]

  57. 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]

  58. Kuttan G, Kuttan R: Reduction of leukopenia in mice by "viscum album" administration during radiation and chemotherapy. Tumori 79 (1): 74-6, 1993.  [PUBMED Abstract]

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