Mistletoe, a semiparasitic plant, holds interest as a potential anticancer agent because extracts derived from it have been shown to kill cancer cells in vitro [1-15] Reviewed in [16,17] and to stimulate immune system cells both in vitro and in vivo. [18-48] Reviewed in [17,49-60] Two components of mistletoe, namely viscotoxins and lectins, may be responsible for these effects.[1,4,7,9-11,13,24,26-28,30-33,35,36,38-42,46-48,61-63] Reviewed in [16,17,43,49-52,54-59,64-67] Viscotoxins are small proteins that exhibit cell-killing activity and possible immune-system–stimulating activity.[7,13,47,48] Reviewed in [50,64] Lectins are complex molecules made of both protein and carbohydrates that are capable of binding to the outside of cells (for example, immune system cells) and inducing biochemical changes in them. Reviewed in [17,51,56,68-71] In view of mistletoe’s ability to stimulate the immune system, it has been classified as a type of biological response modifier. Reviewed in [51] Biological response modifiers constitute a diverse group of biological molecules that have been used individually, or in combination with other agents, to treat cancer or to lessen the side effects of anticancer drugs.

Mistletoe is used mainly in Europe, where commercially available extracts are marketed under a variety of brand names, including Iscador, Eurixor, Helixor, Isorel, Iscucin, Plenosol, and ABNOBAviscum. Some extracts are marketed under more than one name. For example, Iscador, Isorel, and Plenosol are also sold as Iscar, Vysorel, and Lektinol, respectively. All of these products are prepared from Viscum album Loranthacea (Viscum album L. or European mistletoe). They are not available commercially in the United States. (See below for more information concerning U.S. availability of these extracts.)

Mistletoe grows on several types of trees, and the chemical composition of extracts derived from it depends on the species of the host tree (e.g., apple, elm, oak, pine, poplar, and spruce), the time of year harvested, how the extracts are prepared, and the commercial producer.[4,72] Reviewed in [15,49,51,52,54-56]

Mistletoe extracts are prepared as aqueous solutions or solutions of water and alcohol, and they can be fermented or unfermented.[4,13] Reviewed in [8,11,20,37,52,53,72-74] Some extracts are prepared according to homeopathic principles, and others are not. Reviewed in [17,75] In addition, the commercial products can be subdivided according to the species of host tree. For example, Iscador, a fermented aqueous extract of Viscum album L. that is prepared as a homeopathic drug, is marketed as IscadorM (from apple trees), IscadorP (from pine trees), IscadorQ (from oak trees), and IscadorU (from elm trees). Helixor, an unfermented aqueous extract of Viscum album L. that is standardized by its biological effect on human leukemia cells in vitro, is marketed as HelixorA (from spruce trees), HelixorM (from apple trees), and HelixorP (from pine trees). Reviewed in [52] Eurixor, an unfermented aqueous extract of Viscum album L. harvested from poplar trees, is reportedly standardized to contain a specific amount of one of mistletoe’s lectins (i.e., the lectin ML-I; see History section). Reviewed in [52] Some proponents contend the choice of extract should depend on the type of tumor and the gender of the patient.[76] Reviewed in [52,55,77]

Mistletoe extracts are usually given by subcutaneous injection, although administration by other routes (i.e., oral and intrapleural) has been described.[27,36,42,45,46,51,57-59,65,66,76-94] Reviewed in [52,53,55,56,60,75] In most reported studies, subcutaneous injections were given 2 to 3 times a week, but the overall duration of treatment varied considerably.

Viscum album is listed in the Homeopathic Pharmacopoeia of the United States (HPUS), which is the officially recognized compendium for homeopathic drugs in this country.[95] Although the Food and Drug Administration (FDA) has regulatory authority over homeopathic drugs, this authority is usually not exercised unless the drugs are formulated for injection or there is evidence of severe toxicity. At present, the FDA does not allow the importation or distribution of injectable preparations of mistletoe, including homeopathic formulations, except for the purpose of clinical research. The FDA has not approved the use of mistletoe as a cancer treatment.

Before researchers can conduct clinical drug research in the United States, they must file an Investigational New Drug (IND) application with the FDA. IND approval is also required for clinical investigation of homeopathic drugs. The FDA does not disclose information about IND applications or approvals; this information can be released only by the applicants. At present, at least 2 U.S. investigators have IND approval to study mistletoe as a treatment for cancer.[96,97]

In this summary, the mistletoe extract or product used in each study will be specified wherever possible.

References

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43. Fischer S, Scheffler A, Kabelitz D: Oligoclonal in vitro response of CD4 T cells to vesicles of mistletoe extracts in mistletoe-treated cancer patients. Cancer Immunol Immunother 44 (3): 150-6, 1997.  [PUBMED Abstract]
    
    
44. Preisfeld A: Influence of aqueous mistletoe preparations on humoral immune parameters with emphasis on the cytotoxicity of human complement in breast cancer patients. Forsch Komplementarmed 4: 224-8, 1997. 
    
    
45. Chernyshov VP, Omelchenko LI, Heusser P, et al.: Immunomodulatory actions of Viscum album (Iscador) in children with recurrent respiratory disease as a result of the Chernobyl nuclear accident. Complementary Therapy and Medicine 5 (3): 141-6, 1997. 
    
    
46. Heiny BM, Albrecht V, Beuth J: Correlation of immune cell activities and beta-endorphin release in breast carcinoma patients treated with galactose-specific lectin standardized mistletoe extract. Anticancer Res 18 (1B): 583-6, 1998 Jan-Feb.  [PUBMED Abstract]
    
    
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77. Kjaer M: Misteltoe (Iscador) therapy in stage IV renal adenocarcinoma. A phase II study in patients with measurable lung metastases. Acta Oncol 28 (4): 489-94, 1989.  [PUBMED Abstract]
    
    
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83. Salzer G, Denck H: [Randomized study on medicamentous recurrence prophylaxis with 5-fluorouracil and Iscador in resectioned stomach cancer. Results of an intermediate assessment]. Dtsch Z Onkol 11 (5): 130-1, 1979. 
    
    
84. Salzer G: Pleura carcinosis. Cytomorphological findings with the mistletoe preparation iscador and other pharmaceuticals. Oncology 43 (Suppl 1): 66-70, 1986.  [PUBMED Abstract]
    
    
85. Douwes FR, Wolfrum DI, Migeod F: [Results of a prospective randomized study: chemotherapy versus chemotherapy plus "biological response modifier" in metastasizing colorectal carcinoma]. Dtsch Z Onkol 18 (6): 155-64, 1986. 
    
    
86. Dowes FR, Kalden M, Frank G, et al.: [Treatment of advanced colorectal carcinoma: efficacy test of the combination of 5-fluorouracil and tetrahydrofolic acid versus 5-fluorouracil and tetrahydrofolic acid in combination with an optimized Helixor treatment]. Dtsch Z Onkol 21 (3): 63-7, 1988. 
    
    
87. Gutsch J, Berger H, Scholz G, et al.: [Prospective study in radically operated breast cancer with polychemotherapy, Helixor® and untreated controls]. Dtsch Z Onkol 21: 94-101, 1988. 
    
    
88. Bradley GW, Clover A: Apparent response of small cell lung cancer to an extract of mistletoe and homoeopathic treatment. Thorax 44 (12): 1047-8, 1989.  [PUBMED Abstract]
    
    
89. Dold U, Edler L, Mäurer HCh, et al., eds.: [Adjuvant Cancer Therapy in Advanced Non-Small Cell Bronchial Cancer: Multicentric Controlled Studies To Test the Efficacy of Iscador and Polyerga]. Stuttgart, Germany: Georg Thieme Verlag, 1991. 
    
    
90. Heiny BM: [Adjuvant therapy with standardized mistletoe extract reduces leukopenia and improves the quality of life of patients with advanced breast cancer under palliative chemotherapy (VEC regimen)]. Krebsmedizin 12: 1-14, 1991. 
    
    
91. Schaefermeyer G, Schaefermeyer H: Treatment of pancreatic cancer with Viscum album (Iscador): a retrospective study of 292 patients 1986-1996. Complementary Therapy and Medicine 6: 172-7, 1998. 
    
    
92. Kleeberg UR, Brocker EB, Lejeune F, et al.: Adjuvant trial in melanoma patients comparing rlFN-alpha to rlFN-gamma to Iscador to a control group after curative resection of high risk primary (>=3mm) or regional lymphnode metastasis (EORTC 18871). [Abstract] Eur J Cancer 35 (Suppl 4): A-264, s82, 1999. 
    
    
93. Heiny BM, Albrecht V, Beuth J: Stabilization of quality of life with mistletoe lectin-1-standardized extract in advanced colorectal carcinoma. Onkologe 4 (Suppl 1): S35-9, 1998. 
    
    
94. Wetzel D, Schäfer M: Results of a randomised placebo-controlled multicentre study with PS76A2 (standardised mistletoe preparation) in patients with breast cancer receiving adjuvant chemotherapy. [Abstract] Phytomedicine 7 (Suppl 2): A-SL-66, 2000. 
    
    
95. Viscum album. In: Homoeopathic Pharmacopoeia Convention of the United States.: Homoeopathic Pharmacopoeia of the United States. Washington, DC: 2002, Monograph 9444 Visc. 
    
    
96. Mansky PJ, National Center for Complementary and Alternative Medicine: Phase I Study of Gemcitabine and Mistletoe in Patients With Advanced Solid Tumors, NCCAM-02-AT-260, Clinical trial, Active.  [PDQ Clinical Trial]
    
    
97. Rosenzweig S, Kimmel Cancer Center at Thomas Jefferson University - Philadelphia: Phase II Study of Supplemental Treatment With Mistletoe in Patients With Stage IIIB or IV Non-Small Cell Lung Cancer Receiving Palliative Chemotherapy, TJUH-01F.45, Clinical trial, Active.  [PDQ Clinical Trial]
    
    

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