Extract Iscador Research Articles

Biochemical and morphological changes in mouse liver induced by mistletoe toxins

Natural compounds are often characterized by high biological activity and sometimes toxicity. This also applies to compounds contained in the herb mistletoe.The objective of this study was to investigate short-term effects (up to 48 h) of mistletoe toxins on mouse hepatocytes. Standardized mistletoe extract Iscador P was given to female mice as a single injection (0.1 mg/kg b.w., 1 mg/kg b.w., or 2 mg/kg b.w). Activities of lysosomal hydrolases: acid phosphatase, cathepsins D and L, N-acetyl-β-D-hexosaminidase, β-D-glucuronidase, β-D-glucosidase and cytosolic proteases: arginine and leucine aminopeptidases were analyzed in the liver fractions 24 and 48 h after the injection. The morphology of hepatocytes was examined by light and transmission electron microscopy.Iscador P caused a decrease in the activity of all lysosomal hydrolases (except cathepsins) in the lysosomal pellet, and an increase in the activity of both aminopeptidases and β-D-glucuronidase in the cytosol. However, despite membranotropic properties of the viscotoxins, we did not find a significant labilising effect on the lysosomal membranes. Only β-D-glucuronidase activity was relocated to the supernatant of lysosomal fraction. Microscopic examinations revealed that hepatocyte mitochondria were enlarged and increased in number, whereas the surface of the rough endoplasmic reticulum was decreased significantly.

A systematic review and meta-analysis on the survival of cancer patients treated with a fermented Viscum album L. extract (Iscador) – an update of findings

PURPOSE We aimed at updating the evidence found in controlled studies addressing general and event-free survival of cancer patients treated with the fermented mistletoe extract Iscador. METHODS The databases Embase, PubMed, CAMbase, Scopus, AMED and Cochrane were searched for clinical studies on cancer patients treated with Iscador. Quality of studies and risk of bias were evaluated according to the Cochrane guidelines and the Newcastle Ottawa Scale. Outcome data were expressed as hazard ratios (HR) and the respective 95% confidence intervals (CI). Meta-analysis was carried out using a random-effects model. RESULTS Eighty-two controlled studies met the inclusion criteria, of which 32 with 55 strata provided data for extracting HR and CI. The overall HR was 0.59 (95% CI: [0.53; 0.65], p < 0.0001) in favour of Iscador treatment. Heterogeneity of study results was moderate (I2 = 50.9%; p < 0.0001, τ2 = 0.053). Meta-regression did not reveal significant effects of sample size or study design. However, significant differences were found between cancer entities (p < 0.01), with most pronounced effects in cervical (HR = 0.43) and less pronounced effects in lung cancer (HR = 0.84). CONCLUSIONS We found almost identical effects on cancer survival based on a broader database of higher quality. However, none of the studies was blinded and, therefore, there might be risk of performance bias. Implications for cancer survivors are as follows: findings indicate that adjuvant treatment of cancer patients with Iscador can be associated with a better survival.

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 immunoboosting 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, immunosupporting 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.

Viscumins functionally modulate cell motility-associated gene expression.

In Europe extracts from Viscum album L., the European white-berry mistletoe, are widely used as a complementary cancer therapy. Viscumins (mistletoe lectins, ML) have been scrutinized as important active components of mistletoe and exhibit a variety of anticancer effects such as stimulation of the immune system, induction of cytotoxicity, reduction of tumor cell motility as well as changes in the expression of genes associated with cancer development and progression. By microarray expression analysis, quantitative RT-PCR and RT-PCR based validation of microarray data we demonstrate for the Viscum album extract Iscador Qu and for the lectins Aviscumine and ML-1 that in glioma cells these drugs differentially modulate the expression of genes involved in the regulation of cell migration and invasion, including processes modulating cell architecture and cell adhesion. A variety of differentially expressed genes in ML treated cells are associated with the transforming growth factor (TGF)-β signaling pathway or are targets of TGF-β. ML treatment downregulated the expression of TGF-β itself, of the TGF-β receptor II (TGFBR2), of the TGF-β intracellular signal transducer protein SMAD2, and of matrix-metalloproteinases (MMP) MMP-2 and MMP-14. Even if the changes in gene expression differ between Aviscumine, Iscador Qu and ML-1, the overall regulation of motility associated gene expression by all drugs showed functional effects since tumor cell motility was reduced in a ML-dependent manner. Therefore, ML containing compounds might provide clinical benefit as adjuvant therapeutics in the treatment of patients with invasively growing tumors such as glioblastomas.

Abstract 4845: Fraxini and mistletoe lectins inhibit the proliferation of hepatocellular carcinoma by promoting proteasomal degradation of c-Myc

Abstract Mistletoe extracts, including Fraxini, have been used to treat cancer, including hepatocellular carcinoma (HCC), in Europe. However, the mechanism(s) underlying the effect of Fraxini in HCC is(are) inconclusive which hampers its optimal use for the treatment of HCC. We previously reported that Fraxini, and two other mistletoe extracts Iscador Q and M exerted strong antiproliferative and pro-apoptotic activities in Hep3B cells through targeting c-Myc protein. In current study, we examined the efficacy of Fraxini in HCC bearing animals and further investigated the mechanism by which Fraxini down-regulates c-Myc protein. How c-Myc was regulated by Fraxini was investigated by measuring the half-life of c-Myc protein with cycloheximide chase assay, proteasomal degradation and phosphorylation of c-Myc. The antitumor efficacy of the Fraxini was tested in the Hep3B mouse xenograft model and Fraxini was administered subcutaneously. We found that Fraxini dose dependently suppressed the c-Myc protein expression, but did not affect c-Myc mRNA level in Hep3B cells, suggesting Fraxini down-regulates c-Myc through post-translational regulation. Fraxini reduced the half-life of c-Myc protein from control (40 minutes) to 27 minutes. Inhibition of 26S proteasome activity using MG-132 in Hep3B cells notably antagonized Fraxini induced down-regulation of c-Myc, suggesting that Fraxini down-regulated c-Myc by promoting its proteasome degradation. Fraxini decreased phosphorylation of S62 (stabilizing c-Myc) while slightly increased p-cMycT58 (destabilized c-Myc) in Hep3B cells. When Burkitt's lymphoma Raji cells, which are known to host T58 mutation on c-Myc and result in c-Myc stabilization, were treated with Fraxini, Fraxini (up to 20 μg/ml) exerted minimum activity in cell growth and c-Myc protein expression, augmenting that Fraxini is acting on c-Myc phosphorylation sites which resulted in down-regulation c-Myc and elicited anticancer activity in HCC. Additionally, Fraxini injected (s.c.) to mice carrying Hep3B cell xenograft tumors for 2 weeks significantly reduced the average tumor volume (71.8 ± 22.2 mm3) compared to that in the control treated mice (179.0 ± 36.3 mm3, p &amp;lt; 0.05) and lead to reduction of c-Myc protein in the tumor tissues. Intriguingly, mistletoe lectin, a bioactive component in Fraxini, appears to be most effective in inhibiting the proliferation of c-Myc expressing Hep3B cells compared to that of PLC/RF5 cells with limited expression of c-Myc. Mistletoe lectin (1 pg/ml) in the meantime reduced almost 90% c-Myc protein expression in Hep3B cells. In conclusion, since c-MYC gene is required for hepatocyte proliferation and liver tumorigenesis, Fraxini and mistletoe lectin through targeting c-Myc may have great therapeutic potential for patients with advanced HCC and warrant further investigation. The study is supported by the start-up fund of UT MDACC. Citation Format: Yan Jiang, Yong Pan, Patrea R. Rhea, Richard Lee, Zhimin Lu, Peiying Yang. Fraxini and mistletoe lectins inhibit the proliferation of hepatocellular carcinoma by promoting proteasomal degradation of c-Myc. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4845.

Viscum album extracts (Iscador P) in equine sarcoids of horses–results of an RCT 1 and 5 years after treatment

Viscum album extracts (Iscador P) in equine sarcoids of horses–results of an RCT 1 and 5 years after treatment

Safety and Efficacy of the Long-term Adjuvant Treatment of Primary Intermediate- to High-Risk Malignant Melanoma (UICC/AJCC Stage II and III) with a Standardized Fermented European Mistletoe (Viscum album L.) Extract

Mistletoe therapy is the most frequently used complementary treatment in cancer patients in Germany and Switzerland. However, its safety and efficacy were controversially discussed, also in case of malignant melanoma (MM). The present study should evaluate the therapeutic safety and efficacy of a long-term therapy with a standardized fermented European mistletoe (Viscum album L.) extract Iscador (FME) during post-surgical aftercare of primary intermediate to high-risk MM (UICC/AJCC stage II-III) patients and compare it with an untreated parallel control group from the same cohort. The study was designed as a multicenter, comparative, retrolective, epidemiological cohort study with parallel groups, carried out according to the guidelines of Good Epidemiological Practice (GEP). All patients suffered from surgically treated and histopathologically confirmed primary MM in UICC/AJCC stage II-III without distant metastases. In the study group, FME was administered subcutaneously 2-3 times weekly for at least three months, while the untreated control group was merely observed ("watchful waiting"). In both groups some patients also received radio-, chemo-, and/or immunotherapy. The patients were followed until the last visit or until death. Unselected, chronologically ordered, and standardized anonymous data from medical records that satisfied the predefined eligibility criteria were included for the "per protocol" analysis. Safety was assessed by the number of patients with FME-associated adverse drug reactions (ADRs) and by the search for tumor enhancement. The primary endpoint of efficacy was the adjusted tumor-related survival. Secondary end-points were the overall-, the disease-free- and the brain metastasis-free survival. The survival results were analyzed after adjustment for baseline imbalances, treatment regimens and other potential confounders by the Cox proportional hazard regression method. 686 eligible patients (329 FME vs. 357 controls) from 35 centers were observed for a median aftercare of 81 vs. 52 months. The median FME therapy duration was 30 months. At baseline, both groups were comparable concerning demography, tumor history and risk factors for progression. Additional adjuvant chemotherapy was more frequent in the study group, while immunotherapy was more frequent in the control group. Eleven patients (3.3 %) developed systemic ADRs attributed to the FME-treatment, and 42 patients (12.8 %) developed local ADRs, with mild to intermediate (WHO/CTC grade 1-2) ADR severity and spontaneous resolution in most cases. In six patients the ADRs resulted in therapy termination. Life-threatening ADRs, ADR-related mortality or tumor enhancement were not observed. On the contrary, the incidence rate of lung metastases and the adjusted hazard ratio for brain metastases were significantly lower in the FME group. In the course of the study and during aftercare a total of 212 (30.9 %) patients relapsed or progressed, and 107 (15.6 %) died. A significantly longer tumor-related survival was found in the FME group when compared with the untreated controls (unadjusted tumor-related mortality rate 8.9 % vs. 10.7 %, Kaplan-Meier estimate, Log-rank test, p = 0.017), which was confirmed after adjusting for potential confounders by the tumor-related mortality hazard ratio estimate HR (95 % confidence intervals) = 0.41 (0.23-0.71), p = 0.002. The adjusted HR results of the overall survival, disease-free survival, and the brain metastases-free survival were also significantly superior in the FME group. The long-term FME treatment in patients with primary intermediate to high-risk MM appears safe. Tumor enhancement was not observed. When compared with an untreated parallel control group from the same cohort, the results of the FME treatment suggested a significant survival benefit in primary stage II-III MM patients. These results on survival warrant reconfirmation in a prospective randomized clinical trial with optimized study design and treatment conditions.

Nitric Oxide Involvement in the Anti-tumor Effect of Mistletoe (Viscum album L.) Extracts Iscador on Human Macrophages

Lectins from different types of mistletoe (Viscum album, VA) have cytotoxic and immunomodulatory properties that may be relevant in the inhibition of tumor growth. The mechanism of this anti-tumoral activity remains unknown, although recent investigations point out the induction of anti-tumoral cytotoxic T cell activation. In this study therapeutically available mistletoe extracts (Iscador) prepared from Quercus (VA-Q), apple (Malus, VA-M) or pine (Pinus, VA-P) were used to investigate their capacity to induce tumor regression through the modulation of another T helper-1 (Th-1)-mediated anti-tumoral activity: the activation of macrophages. Macrophages are essential targets for both pro- or anti-inflammatory drugs and constitute an essential member of the anti-tumoral immune response. Freshly isolated human monocyte-derived macrophages are activated and various VA extracts are directly incorporated to cultures to assay their properties on the inflammatory and/or tumor cytotoxic responses. The data indicate that immunomodulatory activities of VA extracts differ according to their origin. VA-M and VA-P were able to increase anti-tumoral activity of activated human macrophages, with a possible role for nitric oxide in this effect.

Preclinical Investigations with Mistletoe (Viscum album L.) Extract Iscador

The mistletoe (Viscum album L.) extract Iscador has been shown to be an effective complementary drug in the treatment of cancer patients after surgical removal of the primary tumor. It improved survival, recovery from damage caused by irradiation or cytostatic therapy, and quality of life. Beneficial effects were seen especially as reduction of the side effects caused by basic oncological therapy. In animal tests, clear anti-carcinogenic effects of Iscador were demonstrated as reduction of tumor growth in preformed tumors and as prevention of tumor growth in newly induced tumors. Mainly immune stimulation but also direct cytotoxic activity are believed to be responsible for the anti-carcinogenic activity of Iscador. Other effects seen in patients, such as improved quality of life and improved psychic conditions, are not possible to be tested in animals. Recently, toxicological investigations were performed with Iscador to get more information on possible toxicological effects which can only be evaluated in preclinical studies. Tests examining the acute toxicity, genotoxic effects as well as effects on reproduction were performed. In these studies, no adverse effects of Iscador preparations were detected thus confirming the information on the safety of the extract which has been gained in clinical trials and during more than 80 years of use in human therapy. Iscador has been shown to be essentially safe. No severe adverse events have been reported during many years of use by thousands of patients. Genotoxic effects and effects on reproduction, which cannot be evaluated in clinical use, have been cleared up in animal tests. Iscador was shown to be clearly non-genotoxic and free of relevant toxic effects on reproduction in vivo. In summary, no risk of adverse effects of Iscador during human use is expected.

Viscotoxins, Mistletoe Lectins and their Isoforms in Mistletoe (Viscum album L.) Extracts Iscador

The purpose of the following study was to evaluate the presence of the most frequently investigated pharmacologically active mistletoe compounds, viscotoxins (VT) and mistletoe lectins (ML), in European mistletoe Viscum album L. and in the pharmaceutical mistletoe preparations Iscador. Quantitative analysis of the VT isoforms A1, A2, A3, B, 1-PS, and U-PS in fresh mistletoe plant material from the three European subspecies of V. album, during fermentative extraction of mistletoe and in Iscador showed that the pharmaceutical proceeding specific for the preparation of Iscador warrants a high yield of VT. No degradation or transformation of VT during the production process became apparent. The VT compositions of the three host specific European subspecies of V. album, ssp. album, ssp. abietis, and ssp. austriacum, showed characteristic differences. They ensured the identification of the subspecies specific types of Iscador. ML contents of mistletoe extracts were reduced during fermentative extraction. The quantified contents of total ML were 261 +/- 9.3 ng/ml in Iscador M 5 mg spec. and 391 +/- 18.3 ng/ml in Iscador Qu 5 mg spec. Binding of ML to the glycoprotein asialofetuin (type 1) was found to be temperature dependent. Binding activity was increased to 250 % (ML I) and 410 % (ML II and ML III) respectively by decreasing temperature from 30 degrees C to 4 degrees C. 95% of ML could be eliminated from Iscador by affinity chromatography with immobilised glycoproteins at 0 degrees C. Quantitative extraction of ML from the crude extract and their analysis by SDS-PAGE revealed the presence of about 30 % ML I, 20% ML II, and 50% ML III in Iscador M 5 mg spec. and Iscador Qu 5 mg spec. The annual course of concentrations of ML and VT in the leaves of V. album showed maximal ML contents in December and culminaton of VT in June. Seasonal fluctuations of the composition of mistletoe imply the importance of fixed harvesting seasons.

Absence of Tumor Growth Stimulation in a Panel of 26 Human Tumor Cell Lines by Mistletoe (Viscum album L.) Extracts Iscador in vitro

Mistletoe (Viscum album L.) extracts exhibit antitumor activity based on direct inhibition of tumor growth as well as modulation of immune response. Recent reports suggested potential stimulation of tumor growth at low doses of mistletoe extracts, particularly in hematological tumors and tumors responding to immunotherapy. Therefore, the direct effect of the three mistletoe extracts Iscador M Spezial, Iscador Qu Spezial and Iscador P on tumor growth was investigated in a panel of 26 human tumor cell lines in vitro using cellular proliferation assays. Antitumor activity of the three preparations at high concentrations was investigated in a panel of 12 cell lines. The results showed no evidence of stimulation of tumor growth by any of the three extracts, in particular the five tumor cell lines previously reported to be sensitive to direct mistletoe lectin stimulation. On the contrary, the lectin containing preparations Iscador M Spezial and Iscador Qu Spezial expressed a pronounced antitumor activity exhibiting a nearly identical antitumor profile compared to isolated mistletoe lectin 1.

Molecular Mechanisms Underlying the Immunomodulatory Effects of Mistletoe (Viscum album L.) Extracts Iscador

Viscum album (VA) preparations (Iscador) consist of aqueous extracts from different types of European mistletoe. Biologically active components of VA extracts include mistletoe lectins (ML) and viscotoxins. The treatment with VA extracts or with purified ML has been shown to be associated with tumor regression in several in vivo experimental models of tumoral implantation. The mechanisms underlying the anti-tumoral activity of VA or ML are complex and involve apoptosis, angiogenesis and immunomodulation. This review provides an account of the current status of the understanding of the VA-associated immunomodulation in various cell types including lymphoblastoid, monocytic or endothelial cell lines.

Effects of Mistletoe (Viscum album L.) Extracts Iscador on Cell Cycle and Survival of Tumor Cells

The molecular and cellular mechanisms by which mistletoe (Viscum album L.) extracts exert cytotoxic and immunomodulatory anti-tumoral effects are largely unknown. In this study the hypothesis that Iscador preparations induce tumor regression by cell cycle inhibition and/or interference with apoptotic signaling pathways in cancer cells was investigated. Also a possible effect on angiogenesis, which is a prerequisite for tumor growth in vivo, is studied in endothelial cell cultures. Furthermore, it was examined which apoptotic signaling route(s) is (are) activated by Iscador by studying specific pro-apoptotic proteins in cultured cells. To characterize these properties, 9 human cancer cell lines of different origin, one epidermis derived cell line and 2 endothelial cell cultures were incubated with different concentrations of Iscador Quercus Spezial and Iscador Malus Spezial. Cell cycle kinetic parameters were measured by bromodeoxyuridine (BrdU) pulse labeling and tubulin staining. Apoptotic responses were detected by M30 Cyto-Death or Annexin V/propidium iodide assays. Characterization of the apoptotic pathway(s) was performed by staining cells for amongst others active caspase 3 and cytochrome C (mitochondrial pathway), as well as active caspase 8 (death receptor pathway). The sensitivity to Iscador treatment varies strongly between different cell lines and also ing those derived from small cell lung cancer, and adenocarcinoma of the lung and breast, as well as endothelial cell cultures, Iscador caused early cell cycle inhibition followed by apoptosis in a dose dependent manner. Amongst the low responders are cell lines derived from colorectal carcinoma. In general Iscador Malus exerted a stronger response than Iscador Quercus. Apoptosis was induced by activating the mitochondrial but not the death receptor dependent pathway, at least in case of Iscador Quercus. Iscador Malus also seemed to induce apoptosis via the death receptor route, which may explain the higher sensitivity of cancer and endothelial cells to this preparation.

Gene Expression Profiles of Different Breast Cancer Cells Compared with their Responsiveness to Fermented Mistletoe (Viscum album L.) Extracts Iscador from Oak (Quercus), Pine (Pinus), White Fir (Abies) and Apple Tree (Malus) in vitro

Cytotoxicity assays in vitro (MTT test) showed that the different breast cancer cell lines Kpl-1, MCF-7 and Mfm-223 respond differently to the mistletoe (Viscum album L.) preparations Iscador. Quercus (Qu), Abies (A), Malus (M) and Pinus (P). In order to determine the differences in the responsiveness of the cells more exactly, the gene expression profiles were determined by cells, which were treated with Mistletoe extracts, compared with untreated control cells. Such differences can be analysed in more detail by looking at the gene expression using Human Whole Genome microarray chips (41,000 genes). The results of the transcriptome analyses suggested that Iscador preparations influenced the overregulation of genes regarding immune defense, stress response, apoptosis and cell-cell adhesion pathways. Within the Mfm-223-Zellen was the Genexpression in MCF-7 and Kpl-1. The MCF-7 cells were affected on the genes which are involved in cell-cell contacts whereas Kpl-1 responded to the mistletoe extracts by changing the mRNA levels of the immune and stress response pathways. Concerning the effects of the mistletoe extract, we conclude that Iscador Qu and M have a greater influence on the immune defense and stress response genes whereas Iscador A tends to affect the cell-cell adhesion and cytoskeleton pathways. In summary, cDNA microarray analyses give us information on whether a cancer cell is sensitive to mistletoe extracts in relation to how many genes are significantly overrepresented after mistletoe treatment, and whether a particular mistletoe extract is more effective on a specific cancer cell than the other preparation.

Investigation of the Effect of Mistletoe (Viscum album L.) Extract Iscador on the Proliferation and Apoptosis of Murine Thymocytes

Mistletoe (Viscum album L.) extracts (ME) have been shown to exhibit a bell-shaped curve of immunological efficacy and mistletoe lectins (MLs) were found to play an important role in this phenomenon. The aim of present in vivo study was to investigate the acute- and long-term effect of a standardized ME (Iscador M special) on thymocyte subpopulations and peripheral T cells using a murine (Balb/c) model. In thymus CD4-CD8- double negative (DN), CD4+CD8+ double positive (DP), CD4+ or CD8+ single positive T cells were determined 24 h after a single injection or following a long-term treatment (twice a week for 4 weeks) with three different dilutions of ME which are corresponding to 4.5 ng/ kg, 22.5 ng/kg and 112.5 ng/kg doses of MLs. The apoptosis of the thymocytes was also tested by flow cytometry using Annexin V and propidium iodide. 24 h after a single injection of ME only the lowest dose caused in the blood samples an elevated CD4+/CD8+ ratio and in thymus an enhanced proliferation of DN thymocytes indicating a similar bell-shaped curve of immunological efficacy. After a treatment for four weeks these responses were less intensive indicating that none of the three doses are immunologically optimal. Surprisingly, both in the acute and in the long-term trial only the lower doses induced significant enhancements in the ratio of apoptotic thymocytes. In addition, ME inhibited the dexamethasone (DX)-induced reduction of DN cell count in thymus, as well as the DX-induced decrease of CD4+/CD8+ ratio and CD4+ cell level in peripheral blood. These in vivo results suggest that investigation of thymocytes in vivo can be helpful in the immunological dose-finding since standardized ME is able to modulate the proliferation and apoptosis of thymocytes with a bell-shaped curve of efficacy. In addition, ME may act lymphoprotectively during DX treatment.

Cytostatic and Cytocidal Effects of Mistletoe (Viscum album L.) Quercus Extract Iscador

Mistletoe (Viscum album) extract (Iscador) is used either alone or in combination with chemotherapy or radiotherapy in the treatment of tumor patients. In this study the effects of Viscum album Quercus (VA Qu) extract (1000 ng lectin and 6 microg viscotoxin/ml) in various doses were investigated in an in vitro model with tumor cells: three multiple myeloma (MM) cell lines (OPM-2, RPMI-8226, U-266) and three B cell lymphoma cell lines (U-698, DOHH-2, WSU-1). None of the three B lymphoma cell lines and none of the three multiple myeloma cell lines produced interleukin (IL)-6 spontaneously or after treatment with VA Qu extract. All three multiple myeloma cell lines expressed surface IL-6R and gp130, the B cell lymphomas expressed only gp130. Viscum album/Qu extract markedly downregulated the membrane expression of IL-6R and gp130 in RPMI-8226 (down to 29% and 32%) and the expression of gp130 in WSU-1 (down to 22%). There was a marked reduction of viable cells of RPMI-8226 (down to 28%) and WSU-1 (down to 8 %) at 100 microg/10(6) cells /ml. There was a clear relationship between the inhibition of proliferation and viability: the percentage reductions of the viable cells at 48 and 72 h were similar to those of proliferation at 24 and 48 h, respectively. This means that firstly the proliferation of the tumor cell is inhibited and then afterwards these cells die by apoptosis or necrosis. The inhibitory effect of VA Qu on the proliferation can be termed cytostatic, on the survival cytocidal. VA Qu was more effective in cells having a high proliferation rate than in those with a low proliferation rate. The effective dose range lay between 25 and 100 microg/10(6) cells/ml (5-20 ng lectin/10(6) cells/ml) for all parameters.

In vitro Immunoreactivity towards Lectin-rich or Viscotoxin-rich Mistletoe (Viscum album L.) Extracts Iscador Applied to Healthy Individuals

The aim of the study was to investigate how exposure to mistletoe extracts in vivo may influence cellular immune reactions by peripheral blood mononuclear cells (PBMC). 47 healthy individuals were exposed for twelve weeks either to Iscador Quercus special (IQ; rich in mistletoe lectin [ML]) (n = 16), to Iscador Pinus (IP; poor in ML but rich in viscotoxin) (n = 15), or to placebo (physiological saline) (n = 16). PBMC were isolated before exposure, during exposure in week 4, 8 and 12, as well as 13 weeks after last exposure (week 25) and incubated for 7 days with IQ or IP. Proliferative response and cytokine release were determined (type 1 cytokines: interferon [IFN]-gamma, tumor necrosis factor [TNF]-gamma, type 2 cytokines: interleukin [IL]-5, IL-13, macrophage/ monocyte-cytokines: IL-1, TNFalpha). IP- and IQ incubation of PBMC from non-exposed individuals lead to a significant increase of proliferation and production of all cytokines. There was a significant increase of IQ-induced TNFalpha (but not IL-1) production by PBMC in week 25 in individuals receiv-type 2-cytokines IL-5 and IL-13 significantly decreased during the observation period (p < 0.05 compared to placebo in week 8). These data indicate that IP seems to contain an antigen, which decreases type 2 reactivity. Furthermore, a component present preferentially in IQ seems to activate the production of the monocyte/ macrophage-related cytokine TNFalpha by PBMC. Intriguingly, also in individuals receiving placebo injections immunological alterations were detected during the observation period.

Prospective Controlled Cohort Studies on Long-term Therapy of Ovarian Cancer Patients with Mistletoe (Viscum album L.) Extracts Iscador

Mistletoe extracts such as Iscador are commonly used as complementary/anthroposophic medications for many cancer indications, particularly for solid cancers. The efficacy of this complementary therapy is still controversial. Does long-term therapy with mistletoe extracts Iscador show any effect on survival and psychosomatic self-regulation of patients with ovarian cancer? Prospective recruitment and long-term follow-up in controlled cohort studies. (1) Two randomized matched-pair studies: OvarRand (ovarian cancer patients without distant metastases; 21 pairs) and OvarMetRand (ovarian cancer patients with distant metastases; 20 pairs); patients having no mistletoe therapy were matched for prognostic factors. By paired random allocation, one of the patients of each pair was suggested therapy with mistletoe extracts Iscador to be applied by her attending physician. (2) Two non-randomized matched-pair studies: Ovar (ovarian cancer patients without distant metastases; 75 pairs) and OvarRand (ovarian cancer patients with distant metastases; 62 pairs); patients that already received therapy with mistletoe extracts Iscador were matched by the same criteria to control patients without therapy with mistletoe extracts Iscador. For overall survival in the randomized studies, the effect in favor of therapy with mistletoe extracts Iscador was significant in OvarMetRand but not in OvarRand; hazard ratio estimate and 95% confidence interval: 0.40 (0.15, 1.03) and 0.33 (0.12, 0.92), respectively. In the non-randomized studies Ovar and OvarMet, the results adjusted for relevant prognostic variables were 0.47 (0.31, 0.69) and 0.62 (0.37, 1.05). Psychosomatic self-regulation in the Iscador group increases significantly within 12 months on a scale from 1 to 6 compared with the control group in the randomized study OvarRand as well as in the non-randomized study Ovar on patients with ovarian cancer without distant metastases; estimate of the median difference and 95% confidence interval: 0.58 (0.30, 0.90) and 0.30 (0.05, 0.65), respectively. Mistletoe extracts Iscador might have the effect of prolonging overall survival of ovarian cancer patients. In the short term, psychosomatic self-regulation increases more markedly under Iscador therapy than under conventional therapy alone.

Treatment of equine sarcoid with the mistletoe extract ISCADOR® P (viscum album austriacus) – a double-blind placebo controlled study

Equine Sarcoid (ES) is the most common skin tumour in horses with high recurrence rate. No single universal treatment is effective. Viscum album extracts (VAE) are used as adjunct in the treatment of human cancer. We hypothesized that therapy with VAE (Iscador® P) is also effective in Equine Sarcoids. Of 53 horses with ES, 42 were treated solely with VAE or placebo as monotherapy and 11 were treated after selective excision of ES. Horses were randomly assigned to the VAE (n=32) or placebo group (n=21). Horses received increasing concentrations of VAE from 0.1mg/ml to 20mg/ml or physiological NaCl solution 3 times a week over 105 days s.c. Number, localization, size and type of the ES were documented over 12 months. Cure or improvement rate (decrease of tumour size by 50% or more in at least half of the tumours) were assessed after one year. Sarcoid level assessment included analysis of 1 to 7 clinically relevant sarcoids per horse. In the VAE group, 13 horses (41%) showed improvement. Of these, 9 patients showed complete remission (28%). In the control group only 3 cases (14%), all showing complete remission, were classified as improved. In the VAE group 27 ES (38%) showed complete remission and 48 (67%) improvement after one year compared to 9 ES with complete remission (13%; n.s.) and 17 ES (40%; p&lt;0.01) with improvement in the placebo group. VAE (Iscador® P) represent a safe and effective treatment for ES, particularly in cases with multiple sarcoids.

Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review

BackgroundIn Europe, extracts from Viscum album (VA-E), the European white-berry mistletoe, are widely used to treat patients with cancer.MethodsWe searched several databases such as Cochrane, EMBASE, NCCAM, NLM, DIMDI, CAMbase, and Medline. Inclusion criteria were controlled clinical studies on parameters associated with survival in cancer patients treated with Iscador. Outcome data were extracted as they were given in the publication, and expressed as hazard ratios (HR), their logarithm, and the respective standard errors using standard formulas.ResultsWe found 49 publications on the clinical effects of Iscador usage on survival of cancer patients which met our criteria. Among them, 41 studies and strata provided enough data to extract hazard ratios (HR) and their standard errors (Iscador versus no extra treatment). The majority of studies reported positive effects in favour of the Iscador application. Heterogeneity of study results was moderate (I2 = 38.3%, p < 0.0001). The funnel plots were considerably skewed, indicating a publication bias, a notion which is corroborated by statistical means (AC = -1.3, CI: -1.9 to -0.6, p <= 0.0001). A random effect meta-analysis estimated the overall hazard ratio at HR = 0.59 (CI: 0.53 to 0.66, p < 0.0001). Randomized studies showed less effects than non-randomized studies (ratio of HRs: 1.24, CI: 0.79 to 1.92, p = 0.35), and matched-pair studies gave significantly better results than others (ratio of HRs: 0.33; CI: 0.17 to 0.65, p = 0.0012).ConclusionsPooled analysis of clinical studies suggests that adjuvant treatment of cancer patients with the mistletoe extract Iscador is associated with a better survival. Despite obvious limitations, and strong hints for a publication bias which limits the evidence found in this meta-analysis, one can not ignore the fact that studies with positive effects of VA-E on survival of cancer patients are accumulating. Future studies evaluating the effects of Iscador should focus on a transparent design and description of endpoints in order to provide greater insight into a treatment often being depreciated as ineffective, but highly valued by cancer patients.