Cancer and Mistletoe Treatment
Mistletoe extracts (Viscum album L.) are widely used integrative cancer care treatments, particularly in Europe (1-5). They are an old herbal remedy (6, 7) and were introduced as a cancer treatment in 1920 by Rudolf Steiner and Ita Wegman, founders of Anthroposophic Medicine (8). Viscum album is a hemiparasitic shrub, growing on different host trees. Different preparations are available for the treatment of cancer (currently Abnobaviscum®, Helixor®, Iscador®, Iscucin®, and Lektinol®). They are available from different host trees such as oak, apple, pine, and many others. They are applied parenteral, particularly subcutaneous, but also intravenous, intratumoral, intrapleural, intraperitoneal, and other sites.
Several pharmacologically active compounds have been isolated from VAE, such as mistletoe lectins (ML I, II, and III) (9), viscotoxins (10, 11), oligo- and polysaccharides (12, 13), lipophilic extracts (14), and various others (6, 7). Currently, VAE triterpenes are gaining great interest. (15-19) The most prominent properties of VAE are their cytotoxic and growth-inhibiting effects, in vitro, on a variety of human tumor cell lines, lymphocytes, and fibroblasts (6, 7). The cytotoxic effects of VAE are mainly due to the apoptosis-inducing mistletoe lectins (20-22), while the viscotoxins induce necrotic cell death (21, 23). VAE is also recognized for their immune-modulating activity: In vitro and in vivo studies have demonstrated activation of monocytes/macrophages, granulocytes, natural killer (NK) cells, NK-cell mediated tumor cell lysis, T-cells (especially T-helper-cells), and the induction of various cytokines (6, 7, 24). VAE also downregulates tumor genes, reduces motility and invasiveness of tumor cells [24), and shows antiangiogenetic effects [25). They also possess DNA stabilizing properties, they reduce chromosome damage and improve DNA repair (26-29]. In animals, VAE displays potent antitumor effects when administered either directly into the tumor or systemically (6, 7, 30).
The clinical effectiveness of mistletoe extracts in cancer has been investigated in a great number of studies, among these 43 prospective randomized controlled trials (31-80): They predominantly report significant clinical benefits. With regard to the quality of studies and consistency of results, the best evidence concerning the efficacy of mistletoe therapy exists for the improvement of quality of life, an increase of weight, and improved tolerability of cytoreductive therapies (chemotherapy, radiotherapy, surgery) (33, 81, 82). Regarding survival, a well-designed randomized controlled trial has recently shown a highly significant benefit in advanced pancreatic cancer (32). Other studies showed similar results (30, 83-85). Effectiveness seems to depend on the duration of the mistletoe therapy, in addition to factors relating to dosage, host tree, and choice of preparation. Tumor remissions have been repeatedly observed after the local application of mistletoe extracts. This finding is consistent with the preclinical research on cytotoxicity and treatment of tumors in animals. During customary low-dose mistletoe therapy, tumor remissions are rare exceptions. Tumor remissions have therefore been reported primarily in small studies, case series, and single cases. (e.g. (30, 84, 86-96))
According to highly experienced practitioners, many improved outcomes are possible, with highly individualized and comprehensive treatment schedules – individually adjusted and with selected dosage, preparation, host tree, injection site, time schedule of administration, and supplementation with other interventions. This still needs to be investigated. (97, 98)
Currently, several interesting trials have been started: One large publicly funded confirmative (phase III) randomized controlled trial investigating the influence of mistletoe treatment on survival and health-related quality of life in patients with advanced pancreatic cancer, conducted at several cancer centers in Sweden (NCT02948309). One phase I trial on the safety of intravenous mistletoe infusions in various cancers, conducted at the John Hopkins Hospital in Baltimore (NCT03051477 [99)), funded by the charity organization Believe Big (www.believebig.org). And one large confirmative (phase III) randomized control on the efficacy and safety of intravesical mistletoe extract compared to Mitomycin installation in superficial bladder cancer, conducted in more than 30 German study sites. (100)
Clinical application of mistletoe extracts is safe, even in high dosages (6, 7, 101-106).
IFAEMM Freiburg at the Witten Herdecke University and the Center for Translational Medicine, Medical Center, University of Freiburg
Both Korean and European Mistletoe Lectin Enhances Natural Killer Cell Cytotoxicity via Upregulation of Perforin Expression
Background: Natural killer (NK) cells are crucial components of the innate immune system, providing the first line of defense against pathogens and malignant cells. In a previous study, we demonstrated the prophylactic activity of water extract of Korean mistletoe (Viscum album coloratum) on tumor metastasis. However, the leading compound from the water extract of Korean mistletoe was not clearly addressed.
Objective: The purpose of this research was mainly focused on addressing the effect of Korean mistletoe lectin (KMLC) on NK cell cytotoxicity, and the ability of cytokine secretion as well as its signal transduction, mitogen-activated protein kinase (MAPK) pathway.
Methods: KMLC was used to test NK cell-mediated cytotoxicity in vitro and in vivo. Non-isotope cytotoxicity assay (bis-N, N, N’, N’-tetraacetic acid (BATDA) release assay) was performed to test the cytotoxicity of NK cells against target tumor cells. Receptor expression was checked by flow cytometry analysis and MAPK signal molecules were analyzed by immunoblotting.
Results and conclusions: KMLC at 200 ng/mL increased the cytotoxicity of NK92 cells by 35% compared with untreated cells. KMLC-treated (at 100 ng/mL) mice splenocytes showed a 20% increase in cytotoxic activity. Also, the B chain, one of the subchains of KMLC, increases perforin expression. We demonstrated that the signal transduction controlling NK cell cytotoxicity was mediated by upregulation of the NKG2D receptor and the expression of a cytotoxic effector molecule. These results strongly suggest that KMLC possesses immunological activity, mediated by NK cell activation.
Younghoon Kim, Inbo Kim, Choon-Ho Park, Jong Bae Kim in Asian Pac J Allergy Immunol: 2018 Sep;36(3):175-183. DOI: 10.12932 / AP-030417-0067.
Antitumor Activity of the Korean Mistletoe Lectin is Attributed to Activation of Macrophages and NK Cells
Inhibitory effect of the lectins (KML-C) isolated from Korean mistletoe (KM; Viscum album coloratum and album) on tumor metastases produced by murine tumor cells (B16-BL6 melanoma, colon 26-M3.1 carcinoma, and L5178Y-ML25 lymphoma cells) was investigated in syngeneic mice. An intravenous (i.v.) administration of KML-C (20-50 ng/mouse) 2 days before tumor inoculation significantly inhibited lung metastases of both B16-BL6 and colon 26-M3.1 cells. The prophylactic effect of 50 ng/mouse of KML-C on lung metastasis was almost the same as that of 100 microg/mouse of KM. Treatment with KML-C 1 day after tumor inoculation induced a significant inhibition of not only the experimental lung metastasis induced by B16-BL6 and colon 26-M3.1 cells but also the liver and spleen metastasis of L5178Y-ML25 cells. Furthermore, multiple administration of KML-C given at 3 day-intervals after tumor inoculation led to a significant reduction of lung metastasis and suppression of the growth of B16-BL6 melanoma cells in a spontaneous metastasis model. In an essay for natural killer (NK) cell activity, i.v. administration of KML-C (50 ng/mouse) significantly augmented NK cytotoxicity against Yac-1 tumor cells 2 days after KML-C treatment. In addition, treatment with KML-C (50 ng/mouse) induced tumoricidal activity of peritoneal macrophages against B16-BL6 and 3LL cells. These results suggest that KML-C has an immunomodulating activity to enhance the host defense system against tumors and that its prophylactic and therapeutic effect on tumor metastasis is associated with the activation of NK cells and macrophages.
Taek Joon Yoon, Yung Choon Yoo, Tae Bong Kang, Seong Kyu Song, Kyung Bok Lee, Erk Her, Kyung Sik Song, Jong Bae Kim in: Arch Pharm Res. 2003 Oct;26(10):861-7. doi: 10.1007/BF02980033.
Immunomodulatory Effects of Viscum Album Extracts on Natural Killer Cells: Review of Clinical Trials
Extracts produced from Viscum album L. (mistletoe) are widely used in complementary and in standard medicine in Central and Northern Europe for the treatment of cancer. In many preclinical and clinical studies, Viscum album extracts were shown to exert significant immunomodulatory functions. Natural killer (NK) cells play an important role in cell-mediated immune responses against tumor cells. This article reviews clinical trials that address the influence of the mistletoe extract Iscador® on NK cells and discusses the results with regard to the NK cell functions assayed, to putative underlying mechanisms and the role of different mistletoe components.
Conclusion: Many preclinical and clinical trials demonstrated a positive effect of Iscador® treatment on NK cell function. Mistletoe lectins have an obvious immunomodulating effect and improve specifically TH-1 response and NK cell function and explain the positive findings in clinical trials in cancer patients and people living with HIV infection.
Sibylla Braedel-Ruoff; Review Forsch Komplementmed: in 2010 Apr;17(2):63-73. doi: 10.1159 / 000288702. Epub 2010 Mar 12.
Immunostimulatory Properties of Mistletoe Extracts and Their Application in Oncology
For a long time cancer immunotherapy was overshadowed by chemotherapy and radiotherapy. Recently, “Science”, one of the world’s top scientific journals, named the stimulation of the body’s immune system to fight cancer cells as the “breakthrough of the year”. In Germany, Switzerland, and Austria, extracts derived from mistletoe (Viscum album L.) such as Iscador, Abnobaviscum, Helixor, Iscar, Iscucin, and Israel have been used in oncology for many years. These extracts have immunomodulating and immunostimulating properties, as demonstrated by experimental studies as well as in clinical trials. Our paper aims to present immunological disorders associated with cancer, which can be counteracted by treatment with extracts derived from mistletoe. Although these drugs cannot replace conventional cancer treatment, they improve patients’ quality and length of life.
Sylwia Wrotek, Robert Skawiński, Wiesław Kozak; Postepy Hig Med Dosw: 2014 Oct 23;68:1216-24. doi: 10.5604/17322693.1126850.
Immunomodulatory Effects of Viscum Album Extracts on Natural Killer Cells: Review of Clinical Trials
In Europe, extracts produced from Viscum album L. (mistletoe) are widely used in complementary and standard medicine for the treatment of cancer. In many preclinical and clinical studies, Viscum album extracts were shown to exert immunomodulatory functions. Natural killer (NK) cells play an important role in cell-mediated immune responses against tumor cells. This article reviews clinical trials that address the influence of the mistletoe extract Iscador® but also ABNOBA Viscum® on NK cells and discusses the results with regard to the NK cell functions assayed, to putative underlying mechanisms and the role of different mistletoe components.
Conclusion: Many clinical trials in various malignancies demonstrated a positive clinical effect of Mistletoe lectins treatment on NK cell function with resulting improvement of quality of life and life expectancy which can be explained by the improvement of NK cell activity. Sibylla Braedel-Ruoff in: Review Forsch Komplementmed. 2010 Apr;17(2):63-73. DOI: 10.1159 / 000288702. Epub 2010 Mar 12.
Adjuvant Therapy Using Mistletoe Containing Drugs Boosts the T-cell-mediated Killing of Glioma Cells and Prolongs the Survival of Glioma Bearing Mice
Viscum album L. extracts (VE) are applied as complementary cancer therapeutics for more than one century. Extracts contain several compounds like mistletoe lectins (ML) 1-3 and viscotoxins, but also several minor ingredients. Since ML-1 has been described as one of the main active components harboring antitumor activity, purified native or recombinant ML-1 has been also used in clinical trials in the last years. The present study examined and compared the immune-boosting effects of three ML-1 containing drugs (the extract ISCADOR Qu, the recombinant ML-1 Aviscumine, and purified native ML-1) in the context of the T-cell mediated killing of glioma cells. Additionally, we examined the possible underlying T-cell stimulating mechanisms. Using cocultures of immune and glioma cells, a PCR-based microarray, quantitative RT-PCR, and an antibody-based array to measure cytokines in blood serum, immune-supporting effects were determined. A highly aggressive, orthotopic, immunocompetent syngeneic mouse glioma model was used to determine the survival of mice treated with ISCADOR Qu alone or in combination with tumor irradiation and temozolomide (TMZ). Treatment of glioblastoma (GBM) cells with ISCADOR Qu that contains a high ML concentration, but also viscotoxins and other compounds, as well as with Aviscumine or native ML-1, enhanced the expansion of cancer cell-specific T-cells as well as T-cell-mediated tumor cell lysis, but to a different degree. In GBM cells all three ML-1-containing preparations modulated the expression of immune response associated genes. In vivo, subcutaneous ISCADOR Qu injections at increasing concentration induced cytokine release in immunocompetent VM/Dk-mice. Finally, ISCADOR Qu, if applied in combination with tumor irradiation and TMZ, further prolonged the survival of glioma mice. Our findings indicate that ML-1 containing drugs enhance anti-GBM immune responses and work in synergy with radiochemotherapy. Therefore, adjuvant mistletoe therapy should be considered as an auspicious treatment option for glioma patients.
Sonja Schötterl , Stephan M Huber, Hans Lentzen, Michel Mittelbronn, Ulrike Naumann in: Evid Based Complement Alternat Med, 2018 Aug 27;2018:3928572. doi: 10.1155/2018/3928572. eCollection 2018.
Immune Modulation Using Mistletoe (Viscum Album L.) Extracts Iscador
One repeatedly finds that mistletoe (Viscum album L.) extracts show immune-modulating effects. This is also true in many cases in the experimental setting. Many of the experimental trials cannot, however, be transferred to the clinical situation – or only in a limited way. This work aimed to pursue the question of the extent to which the function of immune-competent cells can be influenced by mistletoe extracts. To do this, 3 clinical studies were carried out. Results from the first two studies will be presented here. In a prospective observational study with defined inclusion and exclusion criteria, the impact of two different doses of Iscador M (Mali) or Iscador Qu (Quercus) on the function and number of T-lymphocytes from tumor patients was studied. The immunological tests took place monthly during the first six months. Thirty-one patients were included in the slow dose group and 36 patients in the group with swift dose escalation. It was postulated that a too swift increase in dosage would lead to stronger local reactions and impairment of the stimulation capacity of T-cells taken ex vivo and incubated for 72 h. The evaluation showed that patients with stronger local reactions at the injection site have an impairment of mitogen-induced stimulation capacity of T-cells. However, patients with stronger local reactions showed a significant decrease of HLA-DR+ T cells as compared to patients In a GCP-conform, controlled bicentric phase II study the aim was to investigate the efficacy of a perioperative intravenous mistletoe extract application on the modulation of operation-induced immune suppression. For this purpose, 105 patients with breast cancer were recruited. At the treatment center, the patients received an infusion of 1 mg Iscador M Spezial before the start of an operation, in addition to normal medication, while this was not practiced at the control center. The primary trial objective was the oxidative burst in granulocytes taken from patients ex vivo before surgery, and 1 and 3 days after. To take account of possible differences in the two groups, propensity scores were used as the basis for a matched pair analysis. It became clear that inhibition of the granulocyte function in the treatment group was significantly less marked (p < 0.001; Wilcoxon). Mistletoe extract-related adverse reactions were not observed. Thus this special form of application could minimize the immune suppression triggered by general anesthesia and operation stress.
Arndt Büssing: Arzneimittelforschung: 2006 Jun;56(6A):508-15. doi: 10.1055 / s-0031-1296818.
Complementary Treatment With Mistletoe Extracts During Chemotherapy: Safety, Neutropenia, Fever, and Quality of Life Assessed in a Randomized Study
Objectives: Evaluate the safety and clinical response of complementary treatment with European mistletoe extracts during chemotherapy.
Design: Monocentric controlled trial with 195 patients randomized into three groups.
Settings/location: National Cancer Research Center of Serbia.
Subjects: Breast cancer patients (stage T1-3N0-2M0) undergoing surgery and adjuvant chemotherapy with six cycles of cyclophosphamide, adriamycin, and 5-fluorouracil.
Interventions: Two different European mistletoe extracts (Helixor A, Iscador M Spez) were injected three times per week during 18 weeks of chemotherapy in the mistletoe group. A five-year follow-up of routine visits was documented in case report forms.
Outcome measures: Safety was assessed by measuring adverse events, body temperature during chemotherapy, and probability of relapse or metastasis in a 5-year follow-up. During chemotherapy, the neutrophil count and quality of life according to EORTC QLQ-C30 were assessed.
Results: The two patient groups receiving different mistletoe treatments were integrated into one mistletoe group for this safety analysis. Patients in the mistletoe group did not develop more fever symptoms than patients in the control group (two short-term events in each group). No significant differences in the probability of relapse or metastasis were measured between the groups (p = 0.7637). The mistletoe group showed a trend toward less neutropenia (p = 0.178) and improved pain and appetite loss scores (p < 0.0001 and p = 0.047, respectively) while having positive, but not significant, impact on other EORTC QLQ-C30 scores.
Conclusions: Mistletoe extracts were safe in this clinical study. Neither did subcutaneous injections induce fever, nor did they influence the frequency of relapse and metastasis within 5 years. This result suggests that mistletoe extracts had no adverse interactions with the anticancer agents used in this study. Furthermore, several side effects of chemotherapy decreased significantly in breast cancer patients.
Florian Pelzer, Wilfried Tröger, Nat J Altern Complement Med: Sep/Oct 2018;24(9-10):954-961. doi: 10.1089/acm.2018.0159.
Plant-Derived Lectins as Potential Cancer Therapeutics and Diagnostic Tools
Cancer remains a global health challenge, with high morbidity and mortality, despite the recent advances in diagnosis and treatment. Multiple compounds were assessed as novel potential anticancer drugs derived from natural sources, including microorganisms, plants, and animals. Lectins, a group of highly diverse proteins of nonimmune origin with carbohydrate-binding abilities, have been detected in virtually all kingdoms of life. These proteins can interact with free and/or cell surface oligosaccharides and might differentially bind cancer cells since the malignant transformation is tightly associated with altered cell surface glycans. Therefore, lectins could represent a valuable tool for cancer diagnosis and be developed as anticancer therapeutics. Indeed, several plant lectins exert cytotoxic effects mainly by inducing apoptotic and autophagic pathways in malignant cells. This review summarizes the current knowledge regarding the basis for the use of lectins in cancer diagnosis and therapy, providing a few examples of plant-derived carbohydrate-binding proteins with demonstrated antitumor effects.
Milena Mazalovska, J Calvin KouokamBiomed Res Int; 2020 May 15;2020:1631394. doi: 10.1155 / 2020 / 1631394. eCollection 2020.
Could Plant Lectins Become Promising Anti-Tumour Drugs for Causing Autophagic Cell Death?
Plant lectins, a group of highly diverse carbohydrate-binding proteins of non-immune origin, are ubiquitously distributed through a variety of plant species and have recently drawn rising attention due to their remarkable ability to kill tumor cells using mechanisms implicated in autophagy. In this review, we provide a brief outline of the structures of some representative plant lectins such as concanavalin A, Polygonatum cyrtonema lectin, and mistletoe lectins. These can target autophagy by modulating BNIP-3, ROS-p38-p53, Ras-Raf, and PI3KCI-Akt pathways, as well as Beclin-1, in many types of cancer cells. In addition, we further discuss how plant lectins can kill cancer cells by modulating autophagic death, for therapeutic purposes. Together, these findings provide a comprehensive perspective concerning plant lectins as promising new anti-tumor drugs, for autophagic cell death in future cancer therapeutics.
Z Liu, Y Luo, T-T Zhou, W-Z Zhang: Cell Prolif; 2013 Oct;46(5):509-15. DOI: 10.1111/cpr.12054. Epub 2013 Aug 24.
Immunomodulating properties of Aqueous Viscum album extracts in vivo and in vitro
Mistletoe extracts have clear immunomodulatory activity. We show that nontoxic concentrations of Viscum album extracts increase natural killer (NK) cell-mediated killing of tumor cells but spare nontarget cells from NK lysis. The compounds responsible for this bioactivity were isolated from mistletoe and characterized. They have low molecular mass and are thermostable and protease-resistant. After complete purification by HPLC, they were identified by tandem MS as viscotoxins A1, A2, and A3 (VTA1, VTA2, and VTA3, respectively). Whereas micromolar concentrations of these viscotoxins are cytotoxic to the targets, the bioactivity concerning NK lysis is within the nanomolar range and differs between viscotoxin isoforms: VTA1 (85 nm), VTA2 (18 nm), and VTA3 (8 nm). Microphysiometry and assays of cell killing indicate that, within such nontoxic concentrations, viscotoxins do not activate NK cells, but act on cell conjugates to increase the resulting lysis.
Tabasco J, Pont F, Fournie JJ, Vercellone French Institute of Health and Medical Research: European Journal of Biochemistry 269(10):2591-600 · June 2002; Source: PubMed.
Impact of Mistletoe Extract Treatment on Quality of Life and Life Expectancy in Breast, Ovarian and Non-Small Cell Lung Cancer Patients. A Prospective Randomized Controlled Clinical Trial
Standardized aqueous mistletoe extracts have been applied to cancer patients for several decades as complementary medicine. A multicenter, randomized, open, prospective clinical trial was conducted in three oncological centers in the People’s Republic of China in Bejing, Shenyang, and Tianjin. Following the guidelines of “Good Clinical Practice” (GCP), this study was performed to get information on efficacy safety and side-effects of the standardized mistletoe extract (SME). Two hundred and thirty-three patients with breast (n=68), ovarian (n=71), and non-small cell lung cancer (NSCLC; n=94) were enrolled in this study. Two hundred and twenty-four patients fulfilled the requirements for final analysis (n=115 treated with SME HELIXOR A; n=109 comprising the control group being treated with the approved immunomodulating phytopharmacon Lentinan). All patients were provided with standard tumor-destructive treatment schedules and complementarily treated with SME or Lentinan during chemotherapy according to the treatment protocol. Biometrically, the patients of the control and SME treatment group were comparable regarding distribution, clinical classification (WHO), and treatment protocols. Analysis was performed according to the “Intention to treat principle”. Quality of life (QoL) was significantly (p<0.05) improved for patients who were complementarily treated with SME, as determined by the questionnaires FLIC (Functional Living Index-Cancer), TCM (Traditional Chinese Medicine Index), and the KPI (Karnofsky Performance Index) in comparison to the control group. Additionally, the occurrence of adverse events (AEs) was less frequent in the SME than in the control group (total number of AEs 52 versus 90 and number of serious AEs 5 versus 10 in study and control group, most of them due to chemotherapy). Only one serious AE was allocated to complementary treatment in each group (1 angioedema in the SME group). All other side-effects of the SME (7 harmless local inflammatory reactions at the subcutaneous injection site, 4 cases with mild fever) were self-limiting and did not demand therapeutic intervention. This study showed that complementary treatment with SME can beneficially reduce the side-effects of chemotherapy in cancer patients and thus improve quality of life and prolong life expectancy.
B K Piao, Y X Wang, G R Xie, U Mansmann, H Matthes, J Beuth, H S Lin: Anticancer Res; Jan-Feb 2004;24(1):303-9.
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