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PubMed1993

[Mistletoe in the treatment of cancer].

Mistletoe (Viscum album) was introduced in the treatment of cancer in 1917. Today, extracts from the plant are used in adjuvant cancer therapy mainly as injections. The most important active agents are lectins, which have cytotoxic and immunostimulating effects. Mistletoe extracts have low toxicity. No fatal side effects have been reported. More than 40 clinical studies have been carried out, mainly at the Lukas Klinik in Switzerland and the Ludvig Boltzmann-Institute in Austria. Most of these studies claim that mistletoe has a positive effect, but were of poor methodological design. Therefore, in the light of our own positive experiences, we recommend a randomized multicentre study to evaluate the effect of mistletoe in cancer treatment.

History, 20th Century↗
PubMedDate not supplied

Mistletoe in immunology and the clinic (short review).

The recent meeting of the AGMIF (Working Group for Mistletoe Therapy and Immunological Research) held in Herdecke, Germany, on October, 3rd, 1997, covered recent developments in the field of immunological and biological properties of Viscum album L., the European mistletoe, which is used for adjuvant cancer treatment. So far, one extract component, the mistletoe lectin (ML)-1, was propagated by some researchers to be the only relevant substance within the extracts. However, immunological activities of other extract components such as polysaccharides, vesicles, chitin-binding lectin and their interactions discussed in the first part, underline the significance of the other components as well. In the second part, clinical evidence for the beneficial effects of subcutaneous and intratumoral application of mistletoe therapy was presented by different working groups. However, further research is of great importance to carefully analyse and characterize the involved molecules and exact mechanisms underlying the beneficial effects reported in this meeting.

Animals↗
PubMed1991

Demonstration of specifically sensitized lymphocytes in patients treated with an aqueous mistletoe extract (Viscum album L.).

Lymphocytes of 25 patients treated with an aqueous mistletoe extract (Viscum album L.) for up to 6 months (group 1), up to 2 years (group 2), and more than 2 years (group 3) were examined in 3- and 7-day cultures for specifically sensitized lymphocytes. The whole extract (HM), the lectin-polysaccharide fraction (HM-LP), and the 'viscotoxin' fraction (HM-V) were added at concentrations ranging from 0.5 micrograms to 12.5 mg extract/ml. Lymphocytes from four of the nine group 2 patients and five of the ten group 3 patients reacted specifically with HM and HM-LP at an optimal dose of 5.0 mg/ml, but did not react with HM-V. Stimulation indices varied between 1.6 and 16. In the patients of group 3 this effect was observed only when their lymphocytes were co-stimulated in the 3-day cultures with phytohemagglutinin (PHA), in contrast to the four patients of group 2 who reacted only in the 7-day cultures with HM-LP without PHA co-stimulation. Patients' lymphocytes had to be protected from mistletoe lectin-induced cytotoxicity by the addition of their own sera containing anti-mistletoe lectin antibodies. Lymphocytes from tumor patients (n = 18) never treated with mistletoe extracts and healthy individuals (n = 18) showed no specific proliferative response when tested in 3- and 7-day cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody Formation↗
PubMed2002

Korean mistletoe lectin-induced apoptosis in hepatocarcinoma cells is associated with inhibition of telomerase via mitochondrial controlled pathway independent of p53.

The extract of European mistletoe (Viscum album, L) has been used in adjuvant chemotherapy of cancer and mistletoe lectins are considered to be major active components. The present work was performed to investigate the effects of Korean mistletoe lectin (Viscum album L. coloratum agglutinin, VCA) on proliferation and apoptosis of human hepatoma cells as well as the underlying mechamisms for these effects. We showed that VCA induced apoptosis in both SK-Hep-1 (p53-positive) and Hep 3B (p53-negative) cells through p53- and p21-independent pathways. VCA induced apoptosis by down-regulation of Bcl-2 and by up-regulation of Bax functioning upstream of caspase-3 in both cell lines. In addition, we observed down-regulation of telomerase activity in both VCA-treated cells. Our results provide direct evidence of the anti-tumor potential of this biological response which comes from inhibition of telomerase and consequent inducing apoptosis. VCA-induced apoptosis is regulated by mitochondrial controlled pathway independently of p53. These findings are important for the therapy with preparation of mistletoe because they show that telomerase-dependent mechanism can be targeted by VCA in human hepatocarcinoma. Taken together, our results suggest that the VCA, considered as a telomerase-inhibitor, can be envisaged as a candidate for enhancing sensitivity of conventional anticancer drugs.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Influence of mistletoe ( Viscum album) extracts on phagocytosis/burst activity of human phagocytes.

The aim of the present study was to examine the in vitro effects of various mistletoe extracts on human phagocytes. Phagocytosis, oxidative burst, and intracellular killing were analyzed by flow cytometry. None of the mistletoe preparations investigated exhibited significant phagocytosis-enhancing properties. Different mistletoe lectin concentrations ranging from 0.025 to 20 ng/ml showed only marginal influence on phagocyte activity. Contrary to the opinion of numerous practitioners of complementary medicine, the mistletoe preparations tested do not enhance phagocytic function.

Candida albicans↗
PubMed2005

Cloning and expression of mistletoe lectin III B-subunit.

Aqueous extracts of mistletoe (Viscum album L.) contain toxic proteins (lectins) MLI (viscumin), MLII, and MLIII. We previously cloned the gene encoding MLIII precursor. In the present study, a gene fragment encoding the carbohydrate-binding subunit of mistletoe toxic lectin MLIII was cloned and expressed in Escherichia coli cells. The structure and immunochemical properties of recombinant MLIII B-subunit were investigated using a panel of monoclonal antibodies against ML-toxins. Sugar-binding activity of recombinant MLIII B-subunit was determined by ELISA. Amino acid sequence analysis of the cloned MLIII compared with known mistletoe toxins and other ribosome-inactivating type II proteins (ricin, abrin a, and nigrin b B-subunits) revealed essential features of the recombinant MLIIIB primary structure that could determine sugar specificity of the lectin as well as immunomodulating and anti-tumor properties of mistletoe extracts.

Amino Acid Sequence↗
PubMed1994

Anti-diabetic properties of the African mistletoe in streptozotocin-induced diabetic rats.

The African mistletoe, Loranthus bengwensis L. (Loranthaceae), has been widely used in Nigerian folk medicine to treat diabetes mellitus. The aqueous extract or infusion (1.32 g/kg per day) of the leaves of this plant parasitic on lemon, Citrus limon (L.) Brum f. (Rutaceae), guava, Psidium guajava L. (Myrtaceae) and jatropha, Jatropha curcas L. (Euphorbiaceae), respectively, were supplied ad libitum to separate groups of both non-diabetic and streptozotocin-induced diabetic rats, as their only source of fluid for a period of 28 days. The infusions of mistletoe parasite on both lemon and guava trees significantly decreased serum glucose levels in non-diabetic (P < 0.05) and diabetic (P < 0.001) rats, whereas that prepared from mistletoe parasitic on jatropha did not. The data indicate that African mistletoe possesses significant anti-diabetic activity in streptozotocin-induced diabetic rats; its anti-diabetic activity appears to be highly dependent on the host plant species.

Animals↗
PubMed2001

Separation of mistletoe lectins based on the degree of glycosylation using boronate affinity chromatography.

A mixture of two mistletoe lectins (MLs) has been separated according to the degree of glycosylation using boronate affinity chromatography. The mistletoe lectins, mistletoe lectin I (MLI) and mistletoe lectin III (MLIII) with degrees of glycosylation of 6.1 and 3.8%, respectively, were used in the investigation. MLI exhibited a higher retention time than MLIII due to its higher degree of glycosylation. Separation was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The developed method may lead to new applications for the boronate affinity technique, as well as provide an alternative separation method for MLs.

Boronic Acids↗
PubMed2006

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. The aim of this work was 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 (Malus) 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 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 reaction 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 centre the patients received an infusion of 1 mg Iscador M Spezial prior to the start of an operation, in addition to normal medication, while this was not practised at the control centre. The primary trial objective was the oxidative burst in granulocytes taken from patients ex vivo prior to surgery, and 1 and 3 days after. In order 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 minimise the immune suppression triggered by anaesthesia and operation stress.

Animals↗
PubMed2000

Hypereosinophilia induced by high-dose intratumoral and peritumoral mistletoe application to a patient with pancreatic carcinoma.

UNLABELLED: A patient with inoperable adenocarcinoma of the pancreas was treated with intraperitumoral and peritumoral injections of a Viscum album L. extract containing 5,700 ng/mL mistletoe lectin, mainly mistletoe lectin 1 (Abnobaviscum Quercus 2) for 5 weeks (1 injection per week). After the third injection (day 22), a marked eosinophilia was observed (1,800 per microliter) that rose to 3,268 per microliter after the fifth injection (day 42). Furthermore, histology performed on day 28 revealed accumulation of eosinophils in ductal lesions and adjacent stroma in addition to the features of ductal adenocarcinoma. In order to investigate whether eosinophilia correlated with immunological features, we analyzed cytokine production of peripheral blood mononuclear cells (PBMC) from this patient after stimulation with antigens known to "unmask" an individual's predisposition for defined immunoreactions, namely purified protein derivative (PPD) as a stimulator of T-helper (TH1)1-cells and tetanus toxoid (TT) as an activator of TH2-cells. PBMC of the patient showed a strong proliferation and production of interleukin (IL)-5 and IL-10 after incubation with TT indicating a type-2 response. Simultaneously, PBMC were induced to proliferate and produce interferon gamma (IFN-gamma) by incubation with PPD suggesting also a type-1 response. These data would readily explain the eosinophilia because eosinophils are effector cells of type-2 reaction but also require type-1 cytokines. Although the overall clinical course of the patient was rapidly progressive, temporary stabilization of the patient's general condition during mistletoe treatment was observed. It is, however, still an open question whether this transient benefit was due to the induction of eosinophilia by a type-2 response. CONCLUSION: Before high-dose intratumoral and peritumoral treatment with a Viscum album L. extract containing mistletoe, lectin 1 can be associated with hypereosinophilia and strong production of TH1 as TH2 cytokines as well.

Adenocarcinoma↗
PubMed2006

Effects of mistletoe extract on murine thymocytes in vivo and on glucocorticoid-induced cell count reduction.

BACKGROUND: Mistletoe extracts are widely used in cancer patients due to their cytostatic and immunomodulatory effects. Essential components include mistletoe lectins which act as biomodulators with proinflammatory and apoptosisinducing effects. This study investigates the acute and longterm effects of standardized mistletoe extract (Iscador(R) M spec 5 mg) on thymocyte subpopulations and peripheral T-cells using a murine (Balb/c) model. MATERIALS AND METHODS: Using cell surface CD4/CD8 staining and flow cytometry, we followed the changes in CD4-CD8- double-negative (DN), CD4(+)CD8(+) double-positive (DP) and CD4(+) or CD8(+) single-positive (SP) T-cells 24 h after single or repeated injections of 3 different dilutions (1:12, 1:60, 1:300) corresponding to 2.1, 0.42 and 0.08 mg/kg of Iscador. Thymocyte apoptosis was detected by flow cytometry using Annexin V and propidium iodide. RESULTS: 24 h after a single injection of the 2 lower doses, the number of DN thymocytes increased significantly with an enhanced ratio of apoptotic cells. Following administration of the lowest dose, in peripheral blood the CD4(+)/CD8(+) ratio was elevated. In the long-term trial, Balb/c mice were treated twice a week with 3 different doses of Iscador +/- 20 mg/kg of dexamethasone (DX), resulting in significantly enhanced DN thymocytes and elevated levels of apoptotic cells after treatment with the 2 lower doses. Iscador also inhibited the DX-induced reduction in the thymic DN cell count, as well as the DX-induced decrease in the CD4(+)/CD8(+) ratio and CD4(+) in the peripheral blood. CONCLUSION: Our results suggest that standardized mistletoe extract modulates proliferation and apoptosis of thymocytes in a dose-dependent manner and may act lymphoprotective during DX treatment.

Animals↗
PubMed2001

Mistletoe lectin-1 increases tumor necrosis factor-alpha release in lipopolysaccharide-stimulated whole blood via inhibition of interleukin-10 production.

We examined the immunomodulatory properties of the mistletoe preparation Lektinol (standardized for mistletoe lectin-1) and recombinant mistletoe lectin-1 (rML-1) in vitro by assessing alterations in the cytokine response of human whole blood. Lektinol or rML-1 alone did not induce any cytokine release in unstimulated whole blood. However, the lipopolysaccharide (LPS)-induced release of tumor necrosis factor (TNF)-alpha was increased, and the secretion of interleukin (IL)-10 was reduced by Lektinol at a mistletoe lectin-1 (ML-1) concentration of 0.5 to 5 ng/ml, whereas the LPS-induced secretion of IL-1 beta, IL-6, IL-12, and interferon-gamma was not affected. Lektinol did not alter the initial phase of TNF-alpha production but sustained TNF-alpha levels longer than in the LPS controls. Recombinant ML-1, but not the recombinant B-chain alone, also increased TNF-alpha release and decreased IL-10 release. We propose that the increase in TNF-alpha release is due to a specific inhibition of IL-10 release by Lektinol. This conclusion is based on the observation that blocking of endogenously formed IL-10 by a neutralizing antibody results in a similar increase of TNF-alpha in the late production phase after LPS stimulation. This hypothesis was also corroborated by the finding that when endogenously formed IL-10 was blocked, Lektinol could no longer increase TNF-alpha release. These results indicate that Lektinol modulates the cytokine response of human whole blood to LPS in a proinflammatory fashion, which can be attributed to ML-1.

Adjuvants, Immunologic↗
PubMed2005

Mistletoe treatment induces GM-CSF- and IL-5 production by PBMC and increases blood granulocyte- and eosinophil counts: a placebo controlled randomized study in healthy subjects.

OBJECTIVE: Various immunological effects have been reported during application of mistletoe preparations. Because these data are heterogeneous, we performed a placebo controlled study to investigate (1) effects on peripheral granulocyte and eosinophil counts, (2) related cytokine levels and (3) whether effects are related to mistletoe lectin (ML). METHODS: 43 volunteers were randomized to receive the mistletoe plant extract Iscador Quercus spezial (IQ), purified ML, IQ which was depleted from ML, or placebo subcutaneously twice per week for 8 weeks. Weekly, differential blood count and every four weeks spontaneous and IQ- and ML-induced cytokine production by peripheral blood mononuclear cells (PBMC) were analyzed. RESULTS: Leukocyte-, granulocyte-, and eosinophil counts were significantly higher during treatment in the IQ- and ML-groups than in the placebo group. Furthermore, a significant increase of antigen-induced production of GM-CSF, IL-5 and IFNgamma by PBMC was observed in the IQ- and ML-group but not in the groups receiving ML-depleted IQ or placebo. Severe side effects did not occur in any of the subjects. CONCLUSIONS: Treatment with IQ or ML stimulates the production of GM-CSF, IL-5 and IFNgamma by PBMC, and this is accompanied by an increase of eosinophil- and granulocyte-counts. These observations may, therefore, open rational therapeutic indications for mistletoe extracts.

Adult↗
PubMedDate not supplied

Quality of life is improved in breast cancer patients by Standardised Mistletoe Extract PS76A2 during chemotherapy and follow-up: a randomised, placebo-controlled, double-blind, multicentre clinical trial.

The objective of this randomised, multicentre, double-blind clinical trial was to investigate the impact of PS76A2, an aqueous mistletoe extract standardised to mistletoe lectins, on quality of life (QoL) in breast cancer patients. A total of 352 patients were randomly allocated to 2 groups receiving PS76A2 (15 ng mistletoe lectin/0.5 ml) or matching placebo twice weekly for 4 to 6 cycles of CMF (cyclophosphamide, methotrexate, fluorouracil) chemotherapy followed by 2 months follow-up. The primary efficacy end-point was the change from baseline of 3 FACT-G subscales (physical, emotional and functional well-being) during the fourth CMF cycle. Secondary measures included GLQ-8 (8 linear analogue self-assessment scales), Spitzer's uniscale and haematological variables. The main variables of safety analysis were adverse events, including injection site reactions and clinical laboratory tests. The results showed that physical, emotional and functional well-being improved upon PS76A2, but deteriorated following placebo. The treatment differences were statistically significant for the 3 subscales as well as for the summary score FACT-G, which was analysed as O'Brien's rank sum of its 3 subscales: The total score increased by 4.40 +/- 11.28, indicating a higher QoL after PS76A2, but decreased by 5.11 +/- 11.77 with placebo (p<0.0001). The GLQ-8 sum of 8 LASA scales was analysed as a summary score of GLQ-5 (sum of item nos. 1, 5, 6, 7, 8) and GLQ-3 (sum of item nos. 2, 3, 4). GLQ-5 characterises typical aspects of QoL, while GLQ-3 consists of 3 side-effects of CMF (feeling sick, numbness or pins and needles, loss of hair). GLQ-5 decreased by 42.9 +/- 125.0 upon PS76A2, indicating an improvement in QoL, but increased by 60.3 +/- 94.0 upon placebo (p<0.0001). GLQ-3 deteriorated in both groups (PS76A2: 13.9 +/- 52.4; placebo: 34.5 +/- 57.0), but the differences in favour of PS76A2 were, nevertheless, statistically significant (p=0.0007). The total score GLQ-8 improved by 28.9 +/- 154.6 after PS76A2 and deteriorated by 94.8 +/- 141.1 after placebo (p<0.0001). Spitzer's uniscale improved by 12.2 +/- 30.7 upon PS76A2 and deteriorated by 10.8 +/- 26.1 with placebo (p<0.0001). After follow-up without chemotherapy, a significant treatment difference in favour of PS76A2 was determined by means of FACT-G, GLQ-8 and Spitzer's uniscale. PS76A2 was well tolerated in this trial, with the exception of slight local reactions in 17.6% of the PS76A2 group. In conclusion, PS76A2 (15 ng mistletoe lectin/0.5 ml twice weekly) was shown to be safe and effective in improving QoL in breast cancer patients during chemotherapy and follow-up.

Adult↗
PubMed1998

Modulation of cellular and humoral immune responses during exposure of healthy individuals to an aqueous mistletoe extract.

Mistletoe extracts have been shown to exert immunomodulatory properties. However, little is known about changes in different immunological parameters during therapy. Aim of our study was, therefore, to investigate the influence of subcutaneous treatment in 8 volunteers who were exposed to an aqueous mistletoe extract (Viscum album Mali; VM) for 8 weeks. During in vivo exposure, VM induced the production of anti-ML-1 antibodies of the IgG-type. A pronounced proliferation of peripheral blood mononuclear cells (PBMC) could be observed in 6 volunteers. However, the activity and time of maximal response varied from one individual to the other. There was no correlation between the cellular and the humoral reactivity and different antigens present in this mistletoe extract may be operative at different levels of the immune system. In order to define more precisely the type of immune response, cytokines were measured in the supernatants of VM-stimulated cell cultures. VM induced the secretion of Th1- (IFN-gamma) or Th2- (IL-4) related cytokines and also the release of TNF-alpha and IL-6. All these different immunological phenomena can be best explained by presentation of mistletoe-related antigens to T- and B-cells via antigen presenting cells in the draining lymph nodes.

Adjuvants, Immunologic↗
PubMed2003

Mistletoe for cancer? A systematic review of randomised clinical trials.

Mistletoe extracts are widely used in the treatment of cancer. The results of clinical trials are however highly inconsistent. We therefore conducted a systematic review of all randomised clinical trials of this unconventional therapy. Eight databases were searched to identify all studies that met our inclusion/exclusion criteria. Data were independently validated and extracted by 2 authors and checked by the 3rd according to predefined criteria. Statistical pooling was not possible because of the heterogeneity of the primary studies. Therefore a narrative systematic review was conducted. Ten trials could be included. Most of the studies had considerable weaknesses in terms of study design, reporting or both. Some of the weaker studies implied benefits of mistletoe extracts, particularly in terms of quality of life. None of the methodologically stronger trials exhibited efficacy in terms of quality of life, survival or other outcome measures. Rigorous trials of mistletoe extracts fail to demonstrate efficacy of this therapy.

Clinical Trials as Topic↗
PubMed1986

Effects of mistletoe (Viscum album L.) extracts on cultured tumor cells.

Bacterially fermented mistletoe preparations (BFMP) were tested on rat hepatoma tissue culture (HTC) cells and human leukemia Molt 4 cells. A dose-dependent inhibition of the growth rate of the cells was observed. For both cell lines, cytostatic concentrations, expressed in weight of fresh plant, were 0.5 mg/ml culture medium for oak BFMP and 1 mg/ml for apple tree BFMP. However, the action of the two preparations was markedly different on each cell line. Non-viable HTC cells were not stained by trypan blue while non-viable Molt 4 cells were fully colored by this reagent. A lysis of cellular membranes of HTC cells was observed by electron microscopy. Furthermore, oak BFMP inhibited the growth of virus transformed 3T3-SV40 cells more than that of non-transformed 3T3 cells. In contrast to BFMP, non-fermented extracts and a purified mistletoe lectin showed a greater inhibition of the growth of Molt 4 cells than of HTC cells. Samples withdrawn at different times during fermentation gradually lost their inhibitory effect on the growth of Molt 4 cells while their action on HTC cells increased up to the 4th day of fermentation. These results are discussed in relation to the cytotoxic substances of mistletoe already characterized.

Animals↗
PubMed1999

Isolation and characterization of biologically active lectin from Korean mistletoe, Viscum album var. Coloratum.

A mistletoe lectin was isolated from water extracts of Korean mistletoe, a subspecies of Viscum album, grown on Quercus mongolica using CM-Sepharose chromatography followed by an affinity chromatography on a concanavalin A-Sepharose column. The compound proved to be a mistletoe lectin II with D-galactose and N-acetyl-D-galactosamine specificity. Matrix-assisted laser desorption time-of-flight mass spectroscopy showed it to have an average molecular mass of 62.7 kDa and to consist of two subunits of 30.6 kDa and 32.5 kDa. It was a basic protein with isoelectric points of 9.4 and 9.6 by capillary isoelectric focusing and was cytotoxic to Molt4 cell.

Humans↗