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PubMed2002

In vivo-induction of antibodies to mistletoe lectin-1 and viscotoxin by exposure to aqueous mistletoe extracts: a randomised double-blinded placebo controlled phase I study in healthy individuals.

BACKGROUND: Several studies have been performed in tumour patients to analyse the immunological response to mistletoe extracts. Considering the fact that these extracts are given subcutaneously in most instances, the kind of application resembles a typical immunization schedule. We therefore wanted to see how those extracts act on immunocompetent cells of healthy individuals hoping that this kind of provocation test may give new informations about a more specific application of these extracts in certain diseases. SUBJECTS/METHODS: 47 healthy individuals were exposed for twelve weeks either to Iscador Quercus special (IQ) known to be rich in mistletoe lectin (ML)-1 (n = 16), to Iscador Pini (IP) being poor in ML-1 but enriched in viscotoxins (n = 15), or to placebo (physiological saline) (n = 16) in a randomised, double-blinded placebo-controlled study. Humoral immunoreactivity was analysed by measuring antibodies towards the two compounds ML-1 and viscotoxin VA2 (VA2). Sera were collected in intervals of four weeks up to week 12 and again three months after last exposure. RESULTS: None of the subjects had antibodies to ML-1 or VA2 before exposure. In week 12, anti-ML-1 antibodies of the IgG-type were found in all 16 IQ-treated individuals but only 6 of the 15 probands exposed to IP. In contrast, anti-VA2 IgG-antibodies could be detected in all individuals of both groups. The antibodies were preferentially of the IgG1 and IgG3 type while antibodies of the IgA and IgM type were produced only in a few probands. Antibodies of the IgE-type occurred only in the IQ-exposed individuals and were directed against ML-1 but not VA2. None of the probands receiving placebo developed antibodies to ML-1 or VA2. Severe side effects were not observed in any of the probands. CONCLUSIONS: These data obtained in healthy individuals clearly indicate that IQ and IP-extracts can induce antigen-specific humoral responses. They may, therefore, provide, a solid basic for the evaluation of the humoral immune response in disease states.

Adult↗
PubMed1977

[Isolation and characterization of mistletoe extracts (Viscum album L.). I. Affinity chromatography of mistletoe extracts on immobilized plasma proteins].

The agglutinating effect of lectin from mistletoe (Viscum album L.) relative to erythrocytes and tumor cells is destroyed or reduced by plasma proteins. There is a competition between lectin receptors of plasma proteins, especially immunoglobulins and erythrocytes, as well as tumor cells. The preparation of insolubilized immunoglobin fractions allows one to separate lectin from the mistletoe extract. There exist chemical connections between the lectin fixed to the adsorbent and part of the toxic components.

Blood Proteins↗
PubMed1996

Stimulation of cytokine production via a special standardized mistletoe preparation in an in vitro human skin bioassay.

The mistletoe preparation Lektinol is standardized with respect to bioactive mistletoe lectin, the active component of mistletoe. This standardized mistletoe preparation and its active components (mistletoe lectins) were compared in the skin2 bioassay in vitro for their capacity to stimulate interleukin 1 alpha and interleukin 6 release from skin analogue tissue, composed of human cells in their naturally secreted matrix. The standardized mistletoe preparation, its basic ingredient, aqueous mistletoe extract, and pure mistletoe lectins all stimulated IL-1 alpha and IL-6 release from skin2 tissues during 24 h incubation. The amounts of cytokines released from various skin2 tissue lots by mistletoe lectin I (ML I) (0.75-8.0 ng/ml) and by the standardized mistletoe preparation remained relatively constant across a series of different batches. Concentration-response curves to the standardized mistletoe preparation and ML I were similar for IL-1 alpha and IL-6 release. The importance of the concentration of mistletoe lectins for the cytokine-releasing action of the standardized mistletoe preparation was confirmed using a neutralizing anti-mistletoe lectin antiserum. CONCLUSIONS. Using the skin2 method it was shown that reproducible stimulation of cytokine release by a standardized mistletoe preparation from batch to batch is one of the notable features of its pharmaceutical quality. This standardized mistletoe preparation therefore represents a preparation with constant immunobiological effects. Mistletoe lectins of the standardized mistletoe preparation are the active substances in the skin2 bioassay. The skin2 method is a reliable quantitative bioassay for determination of immunopharmacological effects.

Biological Assay↗
PubMed2000

[Mistletoe extracts in the therapy of malignant, hematological and lymphatic diseases--a monocentric, retrospective analysis over 16 years].

OBJECTIVE: The aim of the present investigation was to investigate potentials risks of treatment with mistletoe extracts in patients with malignant haematological and lymphatic diseases consulting the Tumour Ambulance of the Community Hospital Herdecke and to evaluate the therapeutic experiences with this treatment. PATIENTS AND METHODS: All 700 patients with these diseases who had been counselled at the Tumour Ambulance of Community Hospital Herdecke since the foundation of the unit were included in a retrospective questionnaire study to collect information on the course of the disease and the survival time. Therapy with mistletoe extracts had been recommended to all patients. The treatment was carried out by the patient's physician outside the hospital. For inclusion into further analysis, information on survival time and mistletoe treatment had to be available. Survival times of patients who had actually received the recommended mistletoe treatment and of patients who had not received the recommended mistletoe treatment were compared (internal comparison). Furthermore, the results were compared to those of conventionally treated patients obtained from the literature (literature comparison). RESULTS: Of 237 patients for whom sufficient data was available, 14 had not been treated with a mistletoe extract. The median survival time was 9.18 years among patients who had received mistletoe compared to 7.54 years among those without. Before a statistical test was carried out, the equivalent distribution of diagnosis in the 2 groups was tested. Regarding this criterion, only 205 patients treated with mistletoe extract and 9 patients not treated with mistletoe extract could be included into the statistical tests of the median survival time. The median survival time was 11.4 years (mistletoe patients) and 8.6 years (patients without mistletoe therapy). The difference was not significant. There were no cases in which mistletoe treatment was associated with deterioration. The comparison with data from the literature yielded very similar survival times among patients not treated with mistletoe extract and those included in our study. CONCLUSION: No indications to risks of a mistletoe therapy on progress of the disease and the survival time could be found. Therefore, no ethical reservations should be opposed to future prospective investigations of mistletoe therapy in patients with malignant haematological diseases.

Female↗
PubMed2004

[Efficacy and safety of long-term complementary treatment with standardized European mistletoe extract (Viscum album L.) in addition to the conventional adjuvant oncologic therapy in patients with primary non-metastasized mammary carcinoma. Results of a multi-center, comparative, epidemiological cohort study in Germany and Switzerland].

OBJECTIVES: The purpose of the study was to evaluate the therapeutic efficacy and safety of long-term complementary therapy in primary, non-metastatic mammary carcinoma patients in UICC stage I-III with a standardized European mistletoe extract (Viscum album L., Iscador, "mistletoe extract") given in addition to conventional adjuvant oncologic therapy (i.e. chemo-, radio-, and hormonal therapy; "conventional therapy"). METHODS: The multicenter, comparative, retrolective, pharmaco-epidemiological cohort study with parallel groups design and randomly selected centers was carried out according to Good Epidemiological Practice (GEP) rules. The test group patients received subcutaneous mistletoe extract injections for at least three months in addition to the conventional therapy, while the control group was treated with conventional therapy only. The patients were followed up for at least three years or until death. The primary endpoint for efficacy was the overall incidence of adverse drug reactions (ADRs) attributed to the conventional therapy. Secondary endpoints were symptoms associated with disease and treatment, as well as the survival. All end-points were adjusted to baseline imbalance, therapy regimen and other confounders by the logistic regression or the Cox proportional hazard regression. Safety was assessed by the number of patients with ADRs attributed to the mistletoe extract treatment, the ADR severity and the evaluation of a possible tumor enhancement. RESULTS: 1442 patients (710 tests and 732 controls) were eligible for the "per protocol" analysis of efficacy and safety. At baseline, the mistletoe extract group had a more advanced disease and worse prognostic factors profile. After a median follow up of 67 vs. 61 months, and a median mistletoe extract therapy duration of 52 months, significantly fewer test group patients (16.3%) than control patients (54.1%) developed one or more ADRs attributed to the conventional therapy (adjusted odds ratio (95% confidence interval, CI): OR = 0.47 (0.32-0.67), p < 0.001). In the mistletoe extract group, several symptoms more frequently disappeared, and the overall estimated survival was significantly longer (adjusted mortality hazard ratio (95% CI): HR = 0.46 (0.22-0.96), p = 0.038). Systemic ADRs attributed to the mistletoe extract treatment developed 0.8%, and local ADRs 17.3% of the patients. The ADR severity was mild to intermediate (WHO/CTC grade 1-2). Severe mistletoe extract therapy-related ADRs or tumor enhancement were not observed. CONCLUSIONS: The results of the present study confirmed the safety of the complementary therapy of patients with primary, non-metastatic mammary carcinoma with a standardized mistletoe extract and showed considerably fewer ADRs attributed to concurrent conventional therapy, as well as reduced disease and treatment-associated symptoms, and suggested a prolonged overall survival in the mistletoe extract group as compared with controls.

Adult↗
PubMed2001

cDNA cloning and sequence analysis of the lectin genes of the Korean mistletoe (Viscum album coloratum).

We previously isolated a lectin of the Korean mistletoe (Viscum album coloratum). The cDNA clones that encode the A- or the B-chain of the Korean mistletoe lectin were cloned by reverse transcriptase polymerase chain reaction (RT-PCR). The mRNAs that were extracted from the Korean mistletoe were amplified, ligated into the pGEM-T easy vector, and screened with a Korean mistletoe lectin-specific probe. The probe was prepared by PCR amplification of the Korean mistletoe DNA using a primer set designed on the basis of amino acid sequences of the Korean mistletoe lectin that we had purified and reported. Unlike a recent report, which states that the European mistletoe lectin gene has no isoforms, several different clones of the A- and B-chains of the Korean mistletoe lectin were cloned from the same primer set. Three clones of each were selected for sequencing. The sizes of the A-chains were 762, 762, and 768 bp, respectively. The B-chain sizes were 798, 789, and 789 bp, respectively. Each of the clones showed significant variation in the amino acids sequence, including the N-linked glycosylation sites of the lectin. The sequence analysis of each of the Korean lectin clones, in comparison with the European mistletoe lectin and the other type II ribosome binding proteins, is discussed in the text. In addition, Southern blot analysis of the Korean mistletoe genomic DNA, restricted by different enzymes and hybridized with the lectin DNA, showed multi-bands, supporting the existence of multicopy genes or a gene family. These data suggest that heterogeneity of the mistletoe lectin is not only introduced by post-translational modifications, but also by expression of isotypes of the lectin genes.

Amino Acid Sequence↗
PubMed1997

Modulation of cytotoxicity and enhancement of cytokine release induced by Viscum album L. extracts or mistletoe lectins.

Cytotoxic effects of Viscum album L. (mistletoe) extracts and mistletoe lectins were studied by light and electron microscopy. The first events observed were membrane perforation and protrusions typical for apoptosis. Inhibition of Molt 4 cell growth was obtained with lectin concentrations in the pg/ml range as long as cells were cultured in serum-free medium. Under this condition, mistletoe lectin-III was about 10 times more cytotoxic than mistletoe lectin-I; mistletoe lectin-II was in between. Lectin cytotoxicity was modulated by human serum from donors who had never been treated with mistletoe preparations and lectin-specific carbohydrates, added at the mmol/l range, particularly D-galactose (or beta-lactose) for mistletoe lectin-I and N-acetyl-galactosamine for mistletoe lectin-II and -III. In addition, at subtoxic concentrations, mistletoe lectin-I, -II and -III enhanced the production of cytokines (tumour necrosis factor-alpha, interleukin-1 alpha) by isolated human monocytes. The experimental results are discussed in relation to the treatment of cancer patients administered with mistletoe extracts.

Antibodies↗
PubMed2004

Preparation of alginate/chitosan microcapsules and enteric coated granules of mistletoe lectin.

The aqueous extract of European mistletoe (Viscum album, L.) has been used in cancer therapy. The purified mistletoe lectins, main components of mistletoe, have demonstrated cytotoxic and immune-system-stimulating activities. Korean mistletoe (Viscum album L. coloratum), a subspecies of European mistletoe, has also been reported to possess anticancer and immunological activities. A galactose- and N-acetyl-D-galactosamine-specific lectin (Viscum album L. coloratum agglutinin, VCA) with Mr 60 kDa was isolated from Korean mistletoe. Mistletoe preparations have been given subcutaneously due to the low stability of lectin in the gastrointestinal (GI) tract. In the present study, we investigated the possibility of alginate/chitosan microcapsules as a tool for oral delivery of mistletoe lectin. In addition, our strategy has been to develop a system composed of stabilizing cores (granules), which contain mistletoe lectin, extract or powder, coated by a biodegradable polymer wall. Our results indicated that successful incorporation of VCA into alginate/chitosan microcapsules has been achieved and that the alginate/chitosan microcapsule protected the VCA from degradation at acidic pH values. And coating the VCA with polyacrylic polymers, Eudragit, produced outstanding results with ideal release profiles and only minimal losses of cytotoxicity after manufacturing step. The granules prepared with extract or whole plant produced the best results due to the stability in the extract or whole plant during manufacturing process.

Administration, Oral↗
PubMed2003

[Retrospective study of malignant melanoma patients treated with mistletoe extracts].

OBJECTIVE: The aim of the present investigation was to analyze survival time and survival rate of all patients with malignant melanoma who had been counseled at the Tumorambulanz Herdecke of the Community Hospital Herdecke. PATIENTS AND METHODS: 284 melanoma patients were included in a retrospective questionnaire study. Only those patients were considered for analysis in whom the prognostic factors histology, tumor localization, and Clark level were known. The data of the study population were compared with patient data obtained from the literature. RESULTS: 94 patients were included in the analysis. 66 of whom had received and 7 had not received mistletoe treatment, in the remaining 21 patients there was no information whether or not mistletoe treatment had been given. Thus, we did our study without a clearly defined internal control group. The median survival time among patients treated with mistletoe had been 14.1 years. The 5- and 10-year survival rates were 80 and 68% for the mistletoe-treated patients, respectively. DISCUSSION: The 5-year survival rate of the mistletoe-treated patients is comparable to that of patients without mistletoe therapy while the 10-year survival rate is a little bit lower. This may be due to the fact that, in contrast to the patients from the relevant literature, 33.3% of the patients suffered from lymph node and/or distant metastases already before counseling the Tumorambulanz Herdecke. Moreover, 50% of our patients had melanoma of Clark level IV in contrast to 22.2% or 31% in the relevant literature. CONCLUSIONS: In spite of the theoretical reservations against mistletoe treatment in melanoma patients, our retrospective analysis did not show any clues about disadvantages of mistletoe treatment in melanoma patients. A controlled prospective study therefore should prove the efficacy of a mistletoe therapy in patients with malignant melanoma.

Female↗
PubMed2004

Spatial and seasonal variation in amino compounds in the xylem sap of a mistletoe (Viscum album) and its hosts (Populus spp. and Abies alba).

In a field study, the composition and concentrations of amino compounds in the xylem sap of the mistletoe, Viscum album L., and in the xylem sap of two host species, an evergreen conifer (Abies alba Mill.) and a deciduous broad-leaved tree (Populus x euramericana), were analyzed. The xylem sap of both hosts and mistletoe contained large, but similar amounts of total organic nitrogen in low molecular weight amino compounds (TONLW). Nevertheless, individual amino compounds accumulated in the xylem sap of mistletoe relative to the host xylem sap, indicating selective uptake. In the xylem sap of Populus, major amino compounds (asparagine (Asn) and glutamine (Gln)) and the bulk parameters, TONLW and proteinogenic amino acids, showed significant seasonal variation. In Abies and in mistletoe on either host, variation of amino compounds in xylem sap was largely explained by inter-annual differences, not by seasonal variation. In both hosts, TONLW in the xylem sap was dominated by Gln. There was a steady decrease in relative abundance of Gln from the host xylem sap to the mistletoe xylem sap and to the stems and leaves of mistletoe. Simultaneously, the abundance of arginine (Arg) increased. Arginine was the predominant amino compound in the stems and leaves of mistletoe, occurring at concentrations previously observed only in leaves of trees exposed to excess nitrogen. We conclude that Gln (2 mol N mol(-1)) delivered by the host xylem sap is converted, in mistletoe, to Arg (4 mol N mol(-1)) and that the organic carbon liberated from Gln contributes significantly to the parasite's heterotrophic carbon gain. Statistical analyses of the data support this conclusion. Accumulation of Arg in mistletoe is an indication of excess N supply as a result of the uptake of amino compounds from the host xylem sap and a lack of phloem uploading.

Abies↗
PubMed2000

Activation of caspase cascades in Korean mistletoe (Viscum album var. coloratum) lectin-II-induced apoptosis of human myeloleukemic U937 cells.

Mistletoe lectins are of high biological activity and exert cytotoxic effects. We have previously shown that Korean mistletoe, Viscum album var. coloratum, lectin-II specifically induces apoptotic cell death in cancer cells, not normal lymphocytes. The destructive mechanism by mistletoe lectins on tumor cells was mediated by activation of c-JUN N-terminal kinase (JNK)/stress-activated protein kinase. Herein, we investigated the involvement of caspase cascade and its proteolytic cleavage effects on biosubstrates of human myeloleukemic U937 cells by D-galactoside and N-acetyl-galactosamine-specific Korean mistletoe lectin-II. Mistletoe lectin-II induced ladder pattern DNA fragmentation and activation of caspase-3, -8, and -9 of U937 cells, but not caspase-1 protease, in a time- and dose-dependent manner. Consistent with catalytic activation of protease, both poly(ADP-ribose) polymerase (PARP) and protein kinase C-delta (PKC-delta) are also cleaved in mistletoe lectin-II-treated U937 cells. An inhibitor of caspase-3-like protease, DEVD-CHO peptide, significantly inhibited mistletoe lectin-II-induced apoptosis, PARP cleavage, and fragmentation of DNA. These results provide the evidence that Korean mistletoe lectin-II induces apoptotic death of U937 cells via activation of caspase cascades.

Adjuvants, Immunologic↗
PubMed2005

Anaphylaxis to viscotoxins of mistletoe (Viscum album) extracts.

BACKGROUND: Extracts of mistletoe (Viscum album) are used in many countries for adjuvant cancer therapy. These extracts contain mistletoe lectins and viscotoxins that are supposed to have immunostimulating and cytotoxic effects, respectively. The treatment is usually well tolerated. OBJECTIVE: To report a case of severe anaphylaxis secondary to mistletoe extract administration with demonstrable anti-IgE antibodies to mistletoe. METHODS: Skin prick tests, basophil histamine release, basophil activation test, and immunoblotting were performed to characterize the pathophysiology of this reaction. RESULTS: The patient had immediate-type skin prick test reactions to the whole commercial preparation and to its mistletoe extract component. A histamine release test and a flow cytometric basophil activation test performed with the patient's peripheral blood leukocytes by incubation with the mistletoe extract yielded a concentration-dependent histamine release and expression of the activation marker gp53 in up to 98% of anti-IgE-positive cells. Immunoblotting revealed IgE binding to 5-kDa proteins of mistletoe in the patient's serum, which corresponds to the molecular weight of viscotoxins. The results of all these tests were negative in controls. CONCLUSIONS: Until now, anaphylaxis to mistletoe extracts has been only rarely reported. In our patient, viscotoxin specific IgE evidently had induced an anaphylactic reaction.

Anaphylaxis↗
PubMed2005

The upward shift in altitude of pine mistletoe (Viscum album ssp. austriacum) in Switzerland--the result of climate warming?

Pine mistletoe (Viscum album ssp. austriacum) is common in natural Scots pine (Pinus sylvestris L.) forests in the alpine Rhone Valley, Switzerland. This semi-parasite, which is regarded as an indicator species for temperature, increases the drought stress on trees and may contribute to the observed pine decline in the region. We recorded mistletoes on representative plots of the Swiss National Forest Inventory ranging from 450 to 1,550 m a.s.l. We found mistletoe on 37% of the trees and on 56% of all plots. Trees infested with mistletoe had a significantly higher mortality rate than non-infested trees. We compared the current mistletoe occurrence with records from a survey in 1910. The current upper limit, 1,250 m, is roughly 200 m above the limit of 1,000-1,100 m found in the earlier survey 100 years ago. Applying a spatial model to meteorological data we obtained monthly mean temperatures for all sites. In a logistic regression mean winter temperature, pine proportion and geographic exposition significantly explained mistletoe occurrence. Using mean monthly January and July temperatures for 1961-1990, we calculated Skre's plant respiration equivalent (RE) and regressed it against elevation to obtain the RE value at the current mistletoe elevation limit. We used this RE value and temperature from 1870-1899 in the regression and found the past elevation limit to be at 1,060 m, agreeing with the 1910 survey. For the predicted temperature rise by 2030, the limit for mistletoe would increase above 1,600 m altitude.

Altitude↗
PubMed2001

Gamma-interferon (IFN-gamma) augments apoptotic response to mistletoe lectin-II via upregulation of Fas/Fas L expression and caspase activation in human myeloid U937 cells.

Mistletoe lectin-II, a major composition of Korean mistletoe (Viscum album coloratum), is known as a potent apoptosis inducer. The previous research has demonstrated that Korean mistletoe lectin-II induces apoptosis via c-Jun N terminal kinase (JNK) activation in human myeloid U937 cells. The purpose of this research is to prove the synergistic action of mistletoe lectin-II and interferon-gamma (IFN-gamma) in the apoptotic cytotoxicity of U937. When U937 cells were treated with mistletoe lectin-II after being differentiated by IFN-gamma, the proteolytic activity of caspase-3 and 9 was markedly elevated and that of caspase-8 was prolonged for 18 hr. The activation of caspase-3-like protease requires the earlier cleavage of poly(ADP-ribose) polymerase(PARP). Caspase-1 was, however, not activated during the resting phase and nor in IFN-gamma-differentiated U937 cells. Western blot analysis revealed that, in IFN-gamma-differentiated U937 cells, the expression of Fas (CD95/APO-1) & Fas ligand(FasL) increases the apoptotic sensitivity against Mistletoe lectin-II. Fas (CD95/APO-1) & FasL were not significantly induced solely by mistletoe lectin-II. Furthermore the activity of JNK1 in U937 cells was also markedly increased with IFN-gamma-differentiation, compared to that of the control. These results suggest that the IFN-gamma-differentiation of U937 cells increases the susceptibility to mistletoe lectin-II-induced apoptosis.

Apoptosis↗
PubMed2006

[Mistletoe (Viscum album) preparations: an optional drug for cancer patients?].

Extracts and preparations from the parasitic plant mistletoe (Viscum album L.) have been used in the treatment of cancer for decades. Mistletoe treatment for cancer was introduced in 1920 by Steiner and Wegman, founders of the Anthroposophical medical method. Today, mistletoe extracts are the most frequently prescribed unconventional cancer therapies in Germany, as in some other European countries. Full clinical data about the efficacy of the mistletoe preparations is still missing. The preparations are usually given as subcutaneous injections, but other routes of administration are also used. Numerous preclinical and in-vitro studies have reported immunostimulatory, cytotoxic and proapoptotic effects. More than 15 prospective clinical trials using mistletoe extracts in patients with different malignancies have been reported. In most of these studies the authors reported that mistletoe extracts had therapeutic benefit in terms of response rate, overall survival, quality of life and reduction in side-effects of the oncological treatment. Unfortunately, almost all of these reported studies had at least one major weakness that questioned their reliability. Side effects of the different mistletoe preparation used in human studies are generally minimal and non-life threatening. In the current review recent studies, including two phase II studies from our center, are included. In the future, data that will be obtained from good quality studies might facilitate reaching firm conclusions regarding the therapeutic benefit of mistletoe preparation for oncological treatment.

Antineoplastic Agents, Phytogenic↗