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At least 19 recordsLinked to original sources

PubMed1989

Influence of carbohydrates on the cytotoxicity of an aqueous mistletoe drug and of purified mistletoe lectins tested on human T-leukemia cells.

Partially and highly purified lectins from Viscum album L. (mistletoe) cause a dose-dependent decrease of viability of human leukemia cell cultures, MOLT-4, after 72 h treatment. The LC50 of the partially purified lectin was 27.8 ng/ml, of the highly purified lectin 1.3 ng/ml. Compared to the highly purified lectin a 140-fold higher protein concentration of an aqueous mistletoe drug was required to obtain similar cytotoxic effects on MOLT-4 cells. Cytotoxicity of the highly purified lectin was preferentially inhibited by D-galactose and lactose, cytotoxicity of the mistletoe drug and the partially purified lectin were preferentially inhibited by lactose and N-acetyl-D-galactosamine (GalNAc). Two lectin fractions with almost the same cytotoxic activity on MOLT-4 cells but with different carbohydrate affinities were isolated by affinity chromatography from the mistletoe drug: mistletoe lectin I with an affinity to D-galactose and GalNAc and mistletoe lectin II with an affinity to GalNAc. The lectin fractions and the mistletoe drug inhibited protein synthesis of MOLT-4 cells stronger than DNA synthesis. Furthermore a subpopulation of MOLT-4, resistant to cytotoxic doses of both the mistletoe drug and the mistletoe lectins, was shown to exhibit a reduced amount of GalNAc and N-acetyl-D-glucosamine in their cellular glycoproteins which are probably responsible for the binding of the cytotoxic lectins. These results indicate that lectins are the main toxins in the mistletoe drug.

Carbohydrates↗

PubMed1997

Induction of anti-mistletoe lectin antibodies in relation to different mistletoe-extracts.

Mistletoe extracts are frequently applied in adjuvant cancer treatment. The mistletoe lectins are especially suggested to mediate an antitumorous effect. During treatment with mistletoe lectin-rich extracts, anti-mistletoe lectin antibodies preferentially of the immunoglobulin G type are produced against mistletoe lectin (ML)-1. Interestingly, after application of mistletoe extracts containing natural micelles, anti-mistletoe lectin antibodies of the immunoglobulin G as well as one of the immunoglobulin E type were induced in parallel, suggesting that the nature and preparation of the antigens within the extract modifies immune responses. Anti-mistletoe lectin antibodies were shown to neutralize the cytotoxic effect of mistletoe lectin on peripheral blood mononuclear cells in vitro. Thus, the mode of application of these extracts seems to be of importance with respect to the therapeutic effect.

Antibodies↗

PubMed1993

In vitro effects of mistletoe extracts and mistletoe lectins. Cytotoxicity towards tumor cells due to the induction of programmed cell death (apoptosis).

The in vitro effects of therapeutically administered mistletoe extracts (ABNOBAviscum) and pure mistletoe lectins (mainly mistletoe lectin I) on a variety of human and murine tumor cell lines have been investigated. Mistletoe extracts and purified mistletoe lectins inhibited in vitro the growth of all tumor cell lines tested including B cell hybridomas, P815, EL-4, Ke37, MOLT-4 and U937. The mechanism of growth arrest was shown to be due to the induction of programmed cell death (apoptosis). Thus, fragmentation of genomic DNA into oligonucleosomal bands of approximately 200 base pairs in length was observed within 20 h when tumor cells were incubated with mistletoe extracts or lectins. These data point to a rational basis for the direct cytotoxic effects of mistletoe extracts and lectins apart from the postulated immunostimulatory properties of these agents.

Adjuvants, Immunologic↗

PubMed1990

Anti-mistletoe lectin antibodies are produced in patients during therapy with an aqueous mistletoe extract derived from Viscum album L. and neutralize lectin-induced cytotoxicity in vitro.

The humoral response components of an aqueous mistletoe extract (HM) was evaluated in 23 tumor patients who had been treated from 2 months up to 6 years with increasing dosages of HM. IgG antibodies against mistletoe lectin and other components of this extract were detected by ELISA, immunodiffusion, and blotting technique, using either the aqueous extract (HM) or a purified lectin preparation (ML). Their activity depended upon dosage of HM and length of therapy. No anti-HM/ML antibodies of the IgM type could be detected. Immunoblotting revealed lectin-specific antigens at 62 kD, 33k D, and 29 kD. In the presence of ML or HM, PHA-induced proliferation of normal lymphocytes was decreased in a dose-dependent manner; this effect was neutralized by adding the IgG fraction from pooled anti-HM-antibody-positive sera, indicating that the cytotoxic effect of lectins was eliminated by these specific antibodies. In view of these findings, it is questionable whether exposing tumor cells to mistletoe extracts in vivo exerts the same direct effect on tumor cells that is observed in vitro.

Blotting, Western↗

PubMed1996

Evaluation of the stimulatory activity of a fermented mistletoe lectin-1 free mistletoe extract on T-helper cells and monocytes in healthy individuals in vitro.

Previously, a strong stimulatory response of peripheral blood mononuclear cells (PBMC) to a fermented mistletoe extract (Iscador Pini, i.p.) could be observed in normal and allergic individuals. Aim of this study was therefore to analyse the cell subtypes involved in this in vitro reactivity. PBMC from 11 non-mistletoe treated healthy and allergic individuals were therefore investigated. Flow cytometric analyses revealed that this mistletoe extract stimulated T-cells (CD3+), especially T-helper cells (CD4+), as well as monocytes at concentrations of 100 or 1,000 micrograms/ml. Furthermore, an increased proportion of T- and T-helper cells expressing the interleukin-2 (IL-2) receptor (CD25) and monocytes expressing HLA-DR molecules, respectively, could be demonstrated. There was no evidence for a major involvement of B- (CD19+), natural killer- (NK-; CD56+) and T-suppressor cells/cytotoxic T-lymphocytes (CD8+). To get more insights whether the T-cell proliferation induced by i.p. was the consequence of a primary or a secondary type of immune response, kinetic studies (n = 5) were performed hereby comparing the reactivity of the non-recall antigen keyhole limpet hemocyanin (KLH) as well as the recall antigen purified protein derivative (PPD) derived from Mycobacterium tuberculosis with that of i.p. I.p. at a concentration of 100 micrograms/ml always exhibited the kinetics of a primary immune reaction. These findings were further substantiated by additional flow cytometric studies analysing changes in the proportions of naive (CD45RA+) and memory/effector cells (CD45RO+) during the exposure to i.p. It could be shown that the proportion of naive cells decreased and that of the transition stage increased, which could indicate that there was a change towards memory/effector cells. In conclusion, these data demonstrate that i.p.-related antigens act like "non-recall"-antigens, and the in vitro immune response involves T-cells as well as monocytes.

Adjuvants, Immunologic↗

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↗

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↗

PubMed1997

Stimulation of the specific immune system by mistletoe extracts.

We have investigated the in vitro responsiveness of T cells from mistletoe-treated cancer patients and untreated donors to various preparations of mistletoe extracts. Proliferation of peripheral blood mononuclear cells from treated but not from untreated patients was observed in response to therapeutically used mistletoe extracts prepared from apple (mali) or pine (pini) host trees. The strongest proliferation was induced by vesicle preparation of mali extract. Using a newly developed flow cytometry assay (standard cell dilution assay), we determined that cell growth was restricted to CD4+ T cells. Analysis with a panel of monoclonal antibodies against variable regions of the T cell receptor beta chain (V beta) revealed an oligoclonal pattern of CD4+ T cell activation. These results indicate that therapeutic administration of mistletoe extracts sensitized a restricted set of CD4+ T lymphocytes in mistletoe-treated patients. Lymphocytes from untreated donors are only stimulated with heat-treated mistletoe extracts. The responding T cells are gamma delta T cells and express variable T cell receptor elements V gamma 9 and V delta 2. The gamma delta-stimulating activity of heat-treated mistletoe extracts is sensitive to treatment with alkaline phosphatase but not with proteinase K, indicating that the ligands are non-proteinaceous phosphate-containing compounds.

Adjuvants, Immunologic↗

PubMedDate not supplied

Treatment of advanced pancreatic cancer with mistletoe: results of a pilot trial.

Pancreatic cancer is a devastating disease with poor prognosis. It is characterized by its unresponsiveness to chemo- and/or radiotherapy. Therefore, many patients demand alternative drug therapy such as mistletoe treatment. However, there are no controlled data available analyzing the effect of mistletoe treatment in pancreatic cancer. In the present phase I/II study we evaluated the effect of mistletoe (Eurixor) treatment in 16 patients (7 women, 9 men) with histologically verified ductal pancreatic carcinoma. At the time when the patients were enrolled nine patients had lymph node metastases (stage III), and in 7 patients distant metastases (stage IV) were present. Mistletoe was administered twice a week by subcutaneous injection in a dosage of 1 ng per kg body weight. Monthly follow-ups included clinical status, multidimensional evaluation of quality of life, contrast enhanced computed axial tomography scan (CT scan) or ultrasonography, and determination of the tumor markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). Apart from one anaphylactic reaction, which necessitated suspension of treatment for a few days, no severe side effects were observed. No partial or complete remission was seen. Eight patients (50%) showed a CT-verified status of "no change" according to World Health Organization criteria for at least 8 weeks. Median survival time in all patients was 5.6 months (range 1.5 to 26.5 months). Analysis of multidimensional evaluation of quality of life showed a stable course of disease in 7 patients. All except two patients claimed that mistletoe had a positive effect on their quality of life, with an obvious decline only during the last weeks of life. These results indicate that mistletoe is not able to significantly influence tumor growth in advanced pancreatic carcinomas. However, mistletoe treatment can stabilize quality of life, and therefore may help patients to maintain adequate life quality in their few remaining months.

Aged↗

PubMed1996

Release of cytokines by a fermented lectin-1 (ML-1) free mistletoe extract reflects differences in the reactivity of PBMC in healthy and allergic individuals and tumour patients.

OBJECTIVE: Mistletoe extracts are used in adjuvant cancer treatment, but little is known concerning their mode of action. There is, however, evidence that antigens in these extracts may stimulate cells of the immune system, thereby modifying the altered immunological reactivity in tumour patients. METHODS: In order to find out whether the postulated immunomodulatory properties of mistletoe extracts are mediated by cytokines, a spectrum of different cytokines was analysed in the supernatants of peripheral blood mononuclear cells (PBMC) from healthy (n = 23) and allergic (n = 16) individuals after stimulation with the fermented mistletoe lectin-1 (ML-1) free mistletoe extract Iscador Pini (IP) in vitro, and their cytokine patterns were compared to those from tumour patients with either breast cancer (n = 20) or colorectal tumours (n = 22). RESULTS: PBMC from healthy and allergic individuals produced high levels of TNF-alpha and IL-6 and to a lesser extent Th1- and Th2-related cytokines. This finding was in contrast to data obtained in tumour patients. Thus, the concentration of TNF-alpha was significantly lower in the cell cultures from breast cancer patients than in controls, and patients with colorectal tumours released IFN-gamma/IL-2 (5%) in the supernatants significantly less frequently than PBMC from healthy controls (26%). Similar results were obtained when the Th1- and monocyte/macrophage-related cytokines were analysed in the unstimulated cell cultures. CONCLUSIONS: These in vitro studies provide evidence that there is a reduced immunological reactivity to the fermented ML-1 free mistletoe extract in tumour patients and may give some clues as to how mistletoe-derived antigens could act on immune cells involved in the tumour defence.

Adult↗

PubMed1990

Characterization of cytotoxic proteins from mistletoe (Viscum album L.).

Proteins from a laboratory-made oak mistletoe extract and from the commercial mistletoe preparation Iscador Quercus were cytotoxic for leukemia Molt 4 cells in culture. A 50% growth inhibition was obtained with 0.1 microgram/ml proteins for the mistletoe extract and 0.025 microgram/ml for Iscador. On cation exchange chromatography, cytotoxic proteins from the mistletoe extract were mainly eluted at the same positions as purified lectins, while those of Iscador were eluted at the positions of viscotoxins. The data are discussed in relation to the pharmacological activities of the mistletoe protein complexes described in the literature.

Antineoplastic Agents, Phytogenic↗

PubMed1997

Donor-dependent and dose-dependent variation in the induction of T lymphocyte locomotion in a three-dimensional collagen matrix system by a mistletoe preparation (Iscador).

Controlled activation of non-specific and specific immune defence mechanisms can beneficially manipulate the host's ability to attack malignant cells. In this context, migration and tissue distribution of immunocompetent cells may be prerequisites for an efficient immune surveillance. The effect of various non-cytotoxic concentrations of the Viscum album L. (mistletoe) preparation Iscadore QuFrF on the locomotory activity of immunomagnetically isolated human CD4+ and CD8+ T lymphocytes from healthy donors was investigated. Cellular migration was examined within a three-dimensional collagen matrix. Donor-dependent variations in baseline activities of spontaneously locomoting T cells were accompanied by individual response patterns of T cells from different donors in the presence of various concentrations of mistletoe preparation (0.25-2.5 micrograms/ml). Using the three-dimensional collagen matrix assay an induction of locomotory activity was detected in a highly reproducible fashion although the optimal concentration of mistletoe preparation and the time point of maximal response were individual for each donor. Our data suggest that the direct stimulation of T-cell migration by mistletoe components may modulate the system of immune surveillance and recognition in patients under mistletoe therapy.

Antineoplastic Agents, Phytogenic↗

PubMed1986

Recent studies on the anticancer activities of mistletoe (Viscum album) and its alkaloids.

Detailed methods for in vitro/in vivo evaluation of anticancer drugs, with special reference to mistletoe extracts, have been reviewed. Mistletoe extracts have been shown to possess significant antitumor activity, in vivo, against murine tumors, Lewis lung carcinoma, colon adenocarcinoma 38 and C3H mammary adenocarcinoma 16/C. Methods for the extraction of biologically active alkaloids from mistletoe and their anticancer activities are presented. The possible origin of alkaloids in mistletoe plants, and their contributions towards a mechanism of anticancer activities of mistletoe extracts, are proposed.

Alkaloids↗

PubMed1986

[Detection and quantitative determination of lectins and viscotoxins in mistletoe preparations].

Mistletoe lectins and viscotoxins, which up to now have been isolated only from plant material, were detected and quantitatively determined in the mistletoe preparation Iscador and in a fermented mistletoe extract. Lectins were isolated by affinity chromatography and analyzed by isoelectric focussing. Thus, in Iscador and in the fermented mistletoe extract only the mistletoe lectins ML II/III were found whereas typical proteins of the ML I complex were missing. The lectin content of the preparation and the extract was determined by "single radial immunodiffusion" (SRID). For identification and quantitative determination of viscotoxins, a HPLC method was designed.

Chromatography, Affinity↗

PubMed1986

Differences in the in vitro effectiveness of preparations produced from mistletoes of various host trees.

The in vitro effectiveness of three Helixor preparations produced from mistletoes of different host trees on suspension cell cultures of the human leukemia cell line Molt 4 has been compared by means of dose-response investigations. After 72 h treatment the preparation produced from mistletoes of the appletree (Malus) shows the strongest effect on the growth and viability of the cell cultures. The preparation produced from mistletoes of the fir (Abies) shows also an evident but much weaker effect, whereas the preparation produced from mistletoes of the pine (Pinus) causes a weak effect only at a very high dosage. As shown in 24-h incorporation experiments with 3H-labelled DNA-, RNA- and protein precursors the preparation produced from mistletoes of the apple-tree reduces the protein synthesis of the cells to a greater extent than the DNA-and RNA-synthesis.

Cell Line↗

PubMedDate not supplied

Immunoprotective activity of the galactoside-specific lectin from mistletoe after tumor destructive therapy in glioma patients.

35 patients suffering from malignant stage III/IV glioma were enrolled into a prospectively randomized clinical trial. All patients were provided with standard oncologic treatment (neurosurgery, radiation, basic clinical care according to protocol and indication) and randomly divided into a) treatment group: receiving subcutaneous injections of a ML (a galactoside-specific lectin from mistletoe) standardized mistletoe extract, 1 ng ML-1/kg BW, twice a week for 3 months, starting on day 1 post surgery, b) control group: without additional complementary treatment. Immunophenotyping of peripheral blood leukocytes was done by flow cytometry (pre surgery; day 1, week 1, month 3 and 6 post surgery) to evaluate the immunomodulating capacity of ML-1 standardized mistletoe extract. Standard tumor destructive treatment of glioma proved to be suppressive for peripheral blood lymphocytes, since all subsets tested revealed statistically significant down regulation. Unlike the lymphocyte counts and activities of patients from the control group who gave preoperative values after 3-6 months), mistletoe treatment induced a statistically significant up regulation of cell counts (CD-3, CD4, CD-8 cells) and activities (CD-25, HLA/DR positive cells) after 3 months, as compared to preoperative values. Obviously, a strong immunoprotective/immunostimulatory effect was induced by the treatment of glioma patients with ML-1 standardized mistletoe extract which correlated with an improved quality of life, as determined by a standard questionnaire (Spitzer).

Brain Neoplasms↗

PubMed1996

Isolation and partial characterization of a small chitin-binding lectin from mistletoe (Viscum album).

A novel lectin, called VisalbCBA, was isolated from European mistletoe (Viscum album). This lectin differs completely from the classical galactose/N-acetylgalactosamine-binding mistletoe lectins MLI, MLII and MLIII. Biochemical analyses indicated that VisalbCBA is a dimeric protein composed of two identical subunits of approx. 10 kDa. VisalbCBA exhibits specificity towards oligomers of N-acetylglucosamine and shows sequence homology to the previously isolated chitin-binding plant proteins. Although VisalbCBA is less toxic than the other mistletoe lectins, it definitely exhibits cytotoxic properties. The possible involvement of VisalbCBA in the biological and therapeutic effects of mistletoe is discussed.

Amino Acid Sequence↗