Standardized Mistletoe Extract 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.

Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro.

BackgroundGiven the importance of complementary and alternative medicine (CAM) to cancer patients, there is an increasing need to learn more about possible interactions between CAM and anticancer drugs. Mistletoe (Viscum album L.) belongs to the medicinal herbs that are used as supportive care during chemotherapy. In the in vitro study presented here the effect of standardized mistletoe preparations on the cytostatic and cytotoxic activity of several common conventional chemotherapeutic drugs was investigated using different cancer cell lines.MethodsHuman breast carcinoma cell lines HCC1937 and HCC1143 were treated with doxorubicin hydrochloride, pancreas adenocarcinoma cell line PA-TU-8902 with gemcitabine hydrochloride, prostate carcinoma cell line DU145 with docetaxel and mitoxantrone hydrochloride and lung carcinoma cell line NCI-H460 was treated with docetaxel and cisplatin. Each dose of the respective chemotherapeutic drug was combined with Viscum album extract (VAE) in clinically relevant concentrations and proliferation and apoptosis were measured.ResultsVAE did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher concentrations VAE showed an additive inhibitory effect.ConclusionsOur in vitro results suggest that no risk of safety by herb drug interactions has to be expected from the exposition of cancer cells to chemotherapeutic drugs and VAE simultaneously.

Can Standardized Plant Extracts Induce Complete Remission in Patients with Metastatic Tumors?

Background: The prognostic significance of malignant tumor-induced imbalance in the innate immune system is well known. The innate system uses a limited number of Pattern Recognition Receptors (PRR) to recognize conserved Pathogenic Associated Molecular Pattern (PAMP) structures expressed by microbes but not by host. PRR engagement often leads to the activation of natural immune cells which are important in the tumor defense. Growing evidence supports the hypothesis that similar to microbes various plant extracts can also contain PAMP-like structures which can activate cellular immune functions. Since the chemical production of PAMP structures is hardly accomplishable, the phytotherapy may be promising for the future tumor therapy. Objectives: The aim of this article is to present and discuss several favorable clinical responses of tumor patients treated with immunologically effective and standardized plant extracts (containing PAMP-like structures) as an addition to the conventional oncologic therapy. Course of therapy and results: Two standardized plant preparations based on lectin-sugar interactions were the patients given. The dose of the active sugar-binding mistletoe lectin (ML), applied subcutaneously by standardized mistletoe extract (ME) preparations, was between 0.5 and 1.0 ng/kg and the dose of arabinoxylan (given by standardized rice bran preparation, MGN-3/Biobran) was between 12 and 45mg/kg twice a week. In addition, wheat germ extract (WGE) standardized for 2, 6-dimethoxy-p-benzoquinone (50-80 mg/kg Avemar four times a week) was also given which can sensitize tumor cells against natural immune effector cells. Case reports gave an account of complete or nearly complete remissions in patients with sarcoma or with hepatic metastases treated with these standardized plant immunomodulators with and without conventional oncologic therapy. Conclusion: Standardized plant extracts (such as ME/ML, MGN-3 and WGE) seem to be potent candidates to be regarded as a supportive therapy of metastatic tumors

Quality of life, immunomodulation and safety of adjuvant mistletoe treatment in patients with gastric carcinoma – a randomized, controlled pilot study

BackgroundMistletoe (Viscum album L.) extracts are widely used in complementary cancer therapy. Aim of this study was to evaluate safety and efficacy of a standardized mistletoe extract (abnobaVISCUM® Quercus, aVQ) in patients with gastric cancer.Patients and Methods32 operated gastric cancer patients (stage Ib or II) who were waiting for oral chemotherapy with the 5-FU prodrug doxifluridine were randomized 1:1 to receive additional therapy with aVQ or no additional therapy. aVQ was injected subcutaneously three times per week from postoperative day 7 to week 24 in increasing doses. EORTC QLQ-C30 and -STO22 Quality of Life questionnaire, differential blood count, liver function tests, various cytokine levels (tumor necrosis factor (TNF)-alpha, interleukin (IL)-2), CD 16+/CD56+ and CD 19+ lymphocytes were analyzed at baseline and 8, 16 and 24 weeks later.ResultsGlobal health status (p <0.01), leukocyte- and eosinophil counts (p ≤0.01) increased significantly in the treatment group compared to the control group. Diarrhea was less frequently reported (7% vs. 50%, p=0.014) in the intervention group. There was no significant treatment effect on levels of TNF-alpha, IL-2, CD16+/CD56+ and CD 19+ lymphocytes and liver function tests measured by ANOVA.ConclusionAdditional treatment with aVQ is safe and was associated with improved QoL of gastric cancer patients. ClinicalTrials.Gov Registration number NCT01401075.

Difficulties and perspectives of immunomodulatory therapy with mistletoe lectins and standardized mistletoe extracts in evidence based medicine

Viscum album preparations are aqueous mistletoe plant extracts used in complementary and alternative medicine as immunomodulators in cancer therapy. However, evidence of immunological efficacy of mistletoe extracts (MEs) used in clinical trials is often lacking. Mechanisms involved in anti-tumor properties of ME and mistletoe lectins (MLs) modify both innate and adaptive immune systems, according to animal model experiments. In the background of these effects, a selective binding of ML on CD75 ganglioside receptors of interleukin 12 (IL-12)-producing macrophages or dendritic cells can play an important role. Immunological effects of ME correlate with their lectin activity, showing a bell-shaped dose-response curve of efficacy. Therefore, a correct determination of MLs for the standardization of commercial ME is essential. However, plant MLs exhibit heterogeneity, which most likely results from post-translational processing. In addition, amino acid analysis of ML has revealed numerous conservative substitutions along their amino acid sequence. Consequently, ML research needs new perspectives, and the advantages and disadvantages of purified and biologically better defined ML preparations are also discussed in this article.

Case reports of sarcoma patients with optimized lectin-oriented and standardized mistletoe extract therapy

Case reports of sarcoma patients with optimized lectin-oriented and standardized mistletoe extract therapy

Lectins are the pharmacologically active constituents in the standardized mistletoe extract PS76A2 (Lektinol ®)

Lectins are the pharmacologically active constituents in the standardized mistletoe extract PS76A2 (Lektinol ®)

Difficulties and Perspectives of Immunomodulatory Therapy with Mistletoe Lectins and Standardized Mistletoe Extracts in Evidence‐Based Medicine

Viscum album preparations are aqueous mistletoe plant extracts used in complementary and alternative medicine as immunomodulators in cancer therapy. However, evidence of immunological efficacy of mistletoe extracts (MEs) used in clinical trials is often lacking. Mechanisms involved in anti-tumor properties of ME and mistletoe lectins (MLs) modify both innate and adaptive immune systems, according to animal model experiments. In the background of these effects, a selective binding of ML on CD75 ganglioside receptors of interleukin 12 (IL-12)-producing macrophages or dendritic cells can play an important role. Immunological effects of ME correlate with their lectin activity, showing a bell-shaped dose-response curve of efficacy. Therefore, a correct determination of MLs for the standardization of commercial ME is essential. However, plant MLs exhibit heterogeneity, which most likely results from post-translational processing. In addition, amino acid analysis of ML has revealed numerous conservative substitutions along their amino acid sequence. Consequently, ML research needs new perspectives, and the advantages and disadvantages of purified and biologically better defined ML preparations are also discussed in this article.

Molecular mechanisms of mistletoe plant extract-induced apoptosis in acute lymphoblastic leukemia in vivo and in vitro

Viscum album (Mistletoe) is one of the most widely used alternative cancer therapies. Aqueous mistletoe extracts (MT) contain the three mistletoe lectins I, II and III as one predominant group of biologically active agents. Although MT is widely used, there is a lack of scientifically sound preclinical and clinical data. In this paper, we describe for the first time the in vivo efficacy and mechanism of action of MT in lymphoblastic leukemia. For this purpose, we first investigated both the cytotoxic effect and the mechanism of action of two standardized aqueous MTs (MT obtained from fir trees (MT-A); MT obtained from pine trees (MT-P)) in a human acute lymphoblastic leukemia (ALL) cell line (NALM-6). MT-A, MT-P and ML-I inhibited cell proliferation as determined by Casy ® Count analysis at very low concentrations with MT-P being the most cytotoxic extract. DNA-fragmentation assays indicated that dose-dependent induction of apoptosis was the main mechanism of cell death. Finally, we evaluated the efficacy of MT-A and MT-P in an in vivo SCID-model of pre-B ALL (NALM-6). Both MTs significantly improved survival (up to 55.4 days) at all tested concentrations in contrast to controls (34.6 days) without side effects.

Tumorwachstumsstimulation durch Mistelpräparate? Fakten und Artefakte

Seit Jahren ist die Frage, ob Mistelpräparate Tumorerkrankungen ungünstig beeinflussen bzw. ein Tumorwachstum stimulieren können, Gegenstand kontroverser Diskussionen. Grundlage für Sicherheitsbedenken ist die Hypothese, dass Mistelpräparate/Mistellektine dosisabhängig zu einer vermehrten Freisetzung pro-inflammatorischer Zytokine (z.B. IL-6) führen, die ein vermehrtes Wachstum bestimmter bösartiger Zellen induzieren könnten. Als Stütze dieser Hypothese werden Ergebnisse einer kleinen Anzahl von In-vitro-Experimenten und Tierversuchen mit Mistellektin I, ein viel diskutierter Einzelfallbericht sowie eine prospektiv-randomisierte, multizentrische EORTC-Melanom-Studie angeführt. Die Resultate der In-vitro-Experimente ließen sich jedoch in umfangreichen neuen Untersuchungsreihen nicht reproduzieren und sind höchstwahrscheinlich als statistische Artefakte zu betrachten. Auch die zitierten Tierversuche ergeben bei genauer Analyse keine Hinweise auf ein Arzneimittelrisiko der Mistel. Die häufig inkorrekt zitierte EORTC-Melanomstudie zeigte sowohl für die Mistelgruppe als auch für die Interferon-Gruppen keinen statistisch signifikanten Unterschied bezüglich krankheitsfreiem und Gesamtüberleben im Vergleich zu der unbehandelten Kontrollgruppe. Die komplementär-onkologische Therapie mit standardisierten Mistelextrakten ist nach heutigem Wissensstand als sicher und unbedenklich einzustufen.

Mistelextrakt in der Nachsorge von Mammakarzinompatientinnen

Grundlage: Prüfung der Unbedenklichkeit und Wirksamkeit einer komplementären Therapie mit dem standardisierten Mistelextrakt Helixor® in der Nachsorge des Mammakarzinoms. Primäres Zielkriterium der Studie war die Evaluation der Lebensqualität.

Safety and Efficacy of Treatment of Breast Cancer Patients with Standardized Mistletoe Extract.

Safety and Efficacy of Treatment of Breast Cancer Patients with Standardized Mistletoe Extract.

Absence of tumor growth stimulation and cytotoxic activity of standardized mistletoe extracts in human tumor cell lines in vitro

Absence of tumor growth stimulation and cytotoxic activity of standardized mistletoe extracts in human tumor cell lines in vitro

Treatment with standardized mistletoe extract (Viscum album L.) Iscador® as a part of long-term supportive care in patients with primary non-metastatic colorectal carcinoma

Aims: Mistletoe therapy is a frequently used supportive treatment in cancer patients to improve quality of life and baseline therapy induced adverse events.

Suppressive Effect of a Standardized Mistletoe Extract on the Expression of Activatory NK Receptors and Function of Human NK Cells

Despite long-term use of mistletoe extracts for cancer treatment, their mode of action remains elusive. In this study, it was studied in vitro if mistletoe extract is able to modulate the expression of natural cytotoxic receptors (NCRs) and NKG2D receptor, which stimulate natural killer cell-mediated cytotoxicity. Unexpectedly, a mistletoe extract, ABNOBA viscum Fraxini, inhibited the expression level of NKp46 and NKG2D receptors in dose- and time-dependent manners. The levels of NKp30 and NKG2D receptors were remarkably induced and NKp44 was slightly induced after 48 h treatment with IL-2 and IL-15 in both mRNA and surface expression. The activatory NK receptors were not induced significantly after treatment with IL-12, IL-18, and IL-21 for 48 h. Induction of activatory NK receptors by IL-2 and IL-15 was suppressed almost to the untreated levels by treatment with mistletoe extract, which appeared to induce apoptosis of NK cells in a dose-dependent manner. However, the treatment with IL-2 and IL-15 did not prevent the mistletoe-induced NK-cell death. Mistletoe extract inhibited significantly the cytotoxic activity of resting and IL-2- or IL-15-stimulated NK cells. These results suggest that inhibition of survival and function of NK cells by mistletoe extract may curtail in part the therapeutic effects of mistletoe.

Successful Treatment of Metastatic Malignant Melanoma with Viscum album Extract (Iscador® M)

Recent study results demonstrate possible clinical benefit from adjuvant treatment with a standardized mistletoe (Viscum album) extract in patients with malignant melanoma. We present a male patient, currently 68 years of age, with one malignant melanoma at the upper part of the right arm since 1992, and another nodular melanoma at the left shoulder, first diagnosed in 1999. After discovery of the second melanoma and surgical resection, the patient was exclusively treated with standardized mistletoe extract (Iscador, (R)M; Weleda AG, CH-Arlesheim, Switzerland). COURSE OF THERAPY AND RESULTS: In June 1992, histologic analysis confirmed the presence of stage IA superficially spreading malignant melanoma with low infiltration of the papillary dermis in a skin excision sample from the upper part of the right arm. In November 1999, another melanoma was surgically removed at the patient's right shoulder. In this case, the histologic examination revealed nodular melanoma, stage IIA (pT3, pN0, M0). Therapy with mistletoe extract was introduced shortly afterwards as the sole adjuvant treatment. During the course of the mistletoe therapy, axillary removal of 8 lymph nodes became necessary, 3 of which proved to be metastatic. First signs of a defined solitary liver metastasis in an area next to segments IV and V were detected during an abdominal ultrasound examination in September 2001. This finding was confirmed by further sonographic examinations. The solitary liver metastasis was not resected, nor was classical antitumor treatment (chemotherapy or radiotherapy) initiated. The patient continued subcutaneous treatment with Iscador M after dose adaptation to 2 mg twice weekly (0.2 mL of a 10-mg vial); the treatment is still ongoing to the present. By June 2002, complete remission of the liver metastasis was diagnosed by liver ultrasound examination. There has been no local relapse so far, and the patient has been in stable condition ever since. No further metastases were discovered so far (as of May 2006). The use of low-dose Iscador as the sole postoperative modality for the adjuvant treatment of metastatic melanoma was extremely effective and very well tolerated in this patient. It achieved complete response and absence of all complaints.

Mistletoe Extract Reduces the Surgical Suppression of Natural Killer Cell Activity in Cancer Patients. A Randomized Phase III Trial

Background: Major surgery suppresses natural killer (NK) cell cytotoxicactivity which is potentially harmful for cancer patients byfavouring haematogenic tumour cell dissemination. The influenceof a perioperative infusion of a standardized mistletoe extract (Iscador®) on immune functions was tested in a prospective, sequential,randomized clinical trial. Patients and Methods: Colorectal cancerpatients undergoing open tumour resection were randomly assignedto either mistletoe infusion or no additional therapy. We hypothesizedthat mistletoe infusion improves NK cell activity andincreases expression of MHC class II antigen HLA-DR on monocytes24 h and 7 days after surgery, respectively. For statistical analysiswe used a sequential study design. The decision boundaries for thetwo triangular tests were calculated for altogether 62 patients. Results:The sequential study design allowed stopping the recruitmentprematurely. NK cell activity differed significantly between the therapygroups 24 h after surgery (p = 0.027). The absolute number ofHLA-DR molecules on monocytes did not differ 7 days after surgery.NK cell activity of patients treated with mistletoe extract did notchange significantly during the course of the study (-7.9% 24 h aftersurgery), whereas HLA-DR expression changed significantly(-38.5% at day 7 after surgery). For control patients both parametersdecreased significantly after surgery (NK cell activity: -44.4% at24 h; HLA-DR expression: -32.9% at day 7 after surgery). Conclusion:Perioperative infusion of mistletoe extracts can prevent a suppressionof NK cell activity in cancer patients. The impact of thistherapy on relapse and survival should be tested in further studies.

Immunologic Effector Mechanisms of a Standardized Mistletoe Extract on the Function of Human Monocytes and Lymphocytes in vitro, ex vivo, and in vivo

Even though mistletoe extracts have been in clinical use for centuries their exact mode of action is still unknown. Currently, the application scheme for registered preparations is a dose-escalating scheme to thus reduce side effects. In this study, healthy controls and patients were evaluated for their immunologic response to treatment with a standardized mistletoe extract (Iscador). It shows a strong effect as adjuvant that induces TNF-alpha and IL-12, which was partly mediated via CD14. Desensitization of the TNF-alpha response could be shown after repeated application in vitro and in vivo. Furthermore, Iscador induces a specific lymphocyte sensitization upon multiple injections and production of IgG1- and IgG3 -mistletoe antibodies. Remarkably, a systemic bystander effect (heterologous immunity against other recall antigens) was observed after long-term treatment. In conclusion, dose-escalation reduces the monocyte-related clinical side effects. A T-lymphocyte sensitization stimulates mainly a specific Th1 response. The most interesting clinical long-term effect is the bystander stimulation of various memory T cells that might mediate in vivo antitumor and antiinfectious T-cell response under mistletoe-extract immunization.

Influence of ML-1 standardized mistletoe extract on the quality of life in head and neck cancer patients

ML-1 standardized mistletoe extracts have been recommended for increasing the health-related quality of life in cancer patients. The EORTC questionnaire QLQ-C30((V2)) was given to a randomly chosen subgroup of 399 patients of a prospective, randomized, open, multi-center trial. A total of 200 patients from this trial were randomized for ML-1 treatment (1 ng/kg body weight ML-1 was injected subcutaneously twice weekly over a 60-week period. Treatment cycles of 12 weeks were followed by a break of 4 weeks (between weeks 12-16, 28-32, and 44-48)). The remaining 199 patients formed the control group. Patients completed questionnaires before the start of their treatments at week 0 and continued until week 156. The compliance rate was high: 3611 questionnaires were available, which equals a median of nine longitudinal measurements per patient between weeks 0 and 156. Analysis did not indicate any improvement in the quality of life for either group. A significant decrease in quality of life, however, was seen in patients undergoing radiotherapy. In these patients, the global state of health was reduced and four symptom scales were significantly worse. Our results demonstrated no improvement in the quality of life in head and neck cancer patients when treated with ML-1 extract.

Effects of Mistletoe Extract on Murine Thymocytes in vivo and on Glucocorticoid-Induced Cell Count Reduction

Background: Mistletoe extracts are widely used in cancerpatients due to their cytostatic and immunomodulatory effects.Essential components include mistletoe lectins whichact as biomodulators with proinflammatory and apoptosisinducingeffects. This study investigates the acute and longtermeffects of standardized mistletoe extract (Iscador® Mspec 5 mg) on thymocyte subpopulations and peripheralT-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 injectionsof 3 different dilutions (1:12, 1:60, 1:300) correspondingto 2.1, 0.42 and 0.08 mg/kg of Iscador. Thymocyteapoptosis was detected by flow cytometry using Annexin Vand propidium iodide. Results: 24 h after a single injectionof the 2 lower doses, the number of DN thymocytes increasedsignificantly with an enhanced ratio of apoptoticcells. Following administration of the lowest dose, in peripheralblood the CD4+/CD8+ ratio was elevated. In thelong-term trial, Balb/c mice were treated twice a week with3 different doses of Iscador +/- 20 mg/kg of dexamethasone(DX), resulting in significantly enhanced DN thymocytes andelevated levels of apoptotic cells after treatment with the2 lower doses. Iscador also inhibited the DX-induced reductionin the thymic DN cell count, as well as the DX-induceddecrease in the CD4+/CD8+ ratio and CD4+ in the peripheralblood. Conclusion: Our results suggest that standardizedmistletoe extract modulates proliferation and apoptosis ofthymocytes in a dose-dependent manner and may act lymphoprotectiveduring DX treatment.