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1.  Safety of Intravenous Application of Mistletoe (Viscum album L.) Preparations in Oncology: An Observational Study 
Background. Traditional mistletoe therapy in cancer patients involves subcutaneous applications of Viscum album L. preparations, with doses slowly increasing based on patient responses. Intravenous infusion of high doses may improve therapeutic outcomes and is becoming more common. Little is known about the safety of this “off-label” application of mistletoe. Methods. An observational study was performed within the Network Oncology. Treatment with intravenous mistletoe applications is described. The frequency of adverse drug reactions (ADRs) to intravenous mistletoe applications was calculated and compared to ADR data from a study on subcutaneous applications. Results. Of 475 cancer patients who received intravenous infusions of Helixor, Abnoba viscum, or Iscador mistletoe preparations, 22 patients (4.6%) reported 32 ADRs of mild (59.4%) or moderate severity (40.6%). No serious ADRs occurred. ADRs were more frequently reported to i.v. mistletoe administered alone (4.3%), versus prior to chemotherapy (1.6%). ADR frequency differed with respect to preparation type, with Iscador preparations showing a higher relative frequency, compared to Abnoba viscum and Helixor. Overall, patients were almost two times less likely to experience an ADR to intravenous compared to subcutaneous application of mistletoe. Conclusion. Intravenous mistletoe therapy was found to be safe and prospective studies for efficacy are recommended.
PMCID: PMC4052504  PMID: 24955100
2.  Safety and effects of two mistletoe preparations on production of Interleukin-6 and other immune parameters - a placebo controlled clinical trial in healthy subjects 
In Germany, Iscucin® Populi (IP), a preparation from mistletoe growing on the poplar tree, is used in cancer therapy while Viscum Mali e planta tota (VM), a preparation from mistletoe growing on the apple tree, is used in patients with osteoarthritis. Since mistletoe preparations are suspected to induce production of potentially tumor promoting cytokines like interleukin (IL)-6, further studies on the immunological effects are of interest.
In this 3-armed randomized, double blind clinical trial healthy volunteers received increasing doses of either IP (strength F, 0.0125%, G, 0.25% and H, 5%, each for 4 weeks), or VM (1:1000 [D3], 1:100 [D2] and 2% each for 4 weeks) or placebo (isotonic solution) subcutaneously twice per week over a period of 12 weeks. Physical examination was performed weekly. Routine laboratory parameters and immunological parameters (C-reactive protein (CRP), differential blood count, lymphocyte subsets, immunoglobulins, IL-6 and tumor necrosis factor (TNF)-α) were analysed every 4 weeks.
71 subjects were included in the study (IP = 30, VM = 21, placebo = 20) of whom 69 concluded it according to protocol. Application of IP strengths G and H caused strong local reactions at the site of injection. In parallel, a distinct eosinophilia (p < 0.001 compared to placebo) occurred. Furthermore, application of all IP concentrations resulted in an increase of CD4 cell counts (p < 0.05) compared to placebo. Stimulation of IL-6 production, CRP or relevant deviations in other laboratory parameters were not observed. Because of local reactions, IP strengths G and H were considered less tolerable than placebo. VM 2% was slightly less tolerable than placebo, caused only mild local reactions and an only small increase in eosinophile counts.
Treatment with IP results in eosinophilia and an increase of CD4 cells but not in an increase of IL-6 or CRP. No safety concerns regarding the two mistletoe preparations have been raised by this study. EudraCT-Number 2007-002166-35.
Trial registration NCT01378702
PMCID: PMC3257204  PMID: 22114899
3.  NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors 
Purpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2 and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.
PMCID: PMC3826324  PMID: 24285980
4.  Mistletoe lectin is not the only cytotoxic component in fermented preparations of Viscum album from white fir (Abies pectinata) 
Preparations of mistletoe (Viscum album) are the form of cancer treatment that is most frequently used in the complementary medicine. Previous work has shown that these preparations are able to exert cytotoxic effects on carcinoma cells, the extent of which might be influenced by the host tree species and by the content of mistletoe lectin.
Using colorimetric assays, we have now compared the cytotoxic effects of Viscum album preparations (VAPs) obtained from mistletoe growing on oak (Quercus robur and Q. petraea, VAP-Qu), apple tree (Malus domestica,, VAP-M), pine (Pinus sylvestris, VAP-P) or white fir (Abies pectinata, VAP-A), on the in vitro growth of breast and bladder carcinoma cell lines. While MFM-223, KPL-1, MCF-7 and HCC-1937 were the breast carcinoma cell lines chosen, the panel of tested bladder carcinoma cells comprised the T-24, TCC-SUP, UM-UC-3 and J-82 cell lines.
Each of the VAPs inhibited cell growth, but the extent of this inhibition differed with the preparation and with the cell line. The concentrations of VAP-Qu, VAP-M and VAP-A which led to a 50 % reduction of cell growth (IC50) varied between 0.6 and 0.03 mg/ml. Higher concentrations of VAP-P were required to obtain a comparable effect. Purified mistletoe lectin I (MLI) led to an inhibition of breast carcinoma cell growth at concentrations lower than those of VAPs, but the sensitivity towards purified MLI did not parallel that towards VAPs. Bladder carcinoma cells were in most cases more sensitive to VAPs treatment than breast carcinoma cells. The total mistletoe lectin content was very high in VAP-Qu (54 ng/mg extract), intermediate in VAP-M (25 ng/mg extract), and very low in VAP-P (1.3 ng/mg extract) and in VAP-A (1 ng/mg extract). As to be expected from the low content of mistletoe lectin, VAP-P led to relatively weak cytotoxic effects. Most remarkably, however, the lectin-poor VAP-A revealed a cytotoxic effect comparable to, or even stronger than, that of the lectin-rich VAP-Qu, on all tested bladder and breast carcinoma cell lines.
The results suggest the existence of cytotoxic components other than mistletoe lectin in VAP-A and reveal an unexpected potential of this preparation for the treatment of breast and bladder cancer.
PMCID: PMC1878504  PMID: 17493268
5.  Quality of Life and Neutropenia in Patients with Early Stage Breast Cancer: A Randomized Pilot Study Comparing Additional Treatment with Mistletoe Extract to Chemotherapy Alone 
Chemotherapy for breast cancer often deteriorates quality of life, augments fatigue, and induces neutropenia. Mistletoe preparations are frequently used by cancer patients in Central Europe. Physicians have reported better quality of life in breast cancer patients additionally treated with mistletoe preparations during chemotherapy. Mistletoe preparations also have immunostimulant properties and might therefore have protective effects against chemotherapy-induced neutropenia.
Patients and Methods:
We conducted a prospective randomized open label pilot study with 95 patients randomized into three groups. Two groups received Iscador® M special (IMS) or a different mistletoe preparation, respectively, additionally to chemotherapy with six cycles of cyclophosphamide, adriamycin, and 5-fluoro-uracil (CAF). A control group received CAF with no additional therapy. Here we report the comparison IMS (n = 30) vs. control (n = 31). Quality of life including fatigue was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Neutropenia was defined as neutrophil counts <1,000/μl and assessed at baseline and one day before each CAF cycle.
In the descriptive analysis all 15 scores of the EORTC-QLQ-C30 showed better quality of life in the IMS group compared to the control group. In 12 scores the differences were significant (p < 0.02) and nine scores showed a clinically relevant and significant difference of at least 5 points. Neutropenia occurred in 3/30 IMS patients and in 8/31 control patients (p = 0.182).
This pilot study showed an improvement of quality of life by treating breast cancer patients with IMS additionally to CAF. CAF-induced neutropenia showed a trend to lower frequency in the IMS group.
PMCID: PMC3086310  PMID: 21556248
mistletoe thereapy; breast cancer; randomized clinical trial; quality of life; neutropenia
6.  Interaction of standardized mistletoe (Viscum album) extracts with chemotherapeutic drugs regarding cytostatic and cytotoxic effects in vitro 
Given 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.
Human 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.
VAE did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher concentrations VAE showed an additive inhibitory effect.
Our 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.
PMCID: PMC3893555  PMID: 24397864
Mistletoe (Viscum album L.); Iscador; Chemotherapy; Drug interactions; Cytostasis; Cytotoxicity
7.  Mistletoe preparation (Viscum Fraxini-2) as palliative treatment for malignant pleural effusion: a feasibility study with comparison to bleomycin 
ecancermedicalscience  2014;8:424.
Malignant pleural effusion is a common problem in patients with solid tumours. It has a significant impact on quality of life, and, hence, there is a substantial need to investigate new agents to treat it.
Patients and methods
This is a prospective randomised controlled study, including patients with symptomatic recurrent malignant pleural effusion of different primaries. Patients were randomised into two groups: the first group received five ampoules of mistletoe preparation with defined lectin content (Viscum Fraxini-2, ATOS Pharma) diluted in 10 cc glucose 5% solution. Re-instillation was repeated every week until complete dryness of the pleural fluid was achieved (the maximum duration of the therapy was eight weeks). The second group received 60 units of bleomycin once intrapleurally.
The primary aim of this paper was to evaluate the efficacy of mistletoe preparation as a palliative treatment for malignant pleural effusions in comparison with bleomycin. The secondary aim was to evaluate the tolerability of the mistletoe preparation.
A total of 23 patients were included and followed up during the study from December 2007 to January 2012: 13 patients received mistletoe preparation, and ten patients received bleomycin. Overall clinical response was reported in 61.5% of the mistletoe preparation arm versus 30% in bleomycin arm (p = 0.2138), 95% CI = (–0.1203, 0.6325). The toxicity of both arms was mild and manageable; the mistletoe preparation arm included fever, chills, headache, malaise, and, in two cases, allergic reaction, which was controlled by discontinuation of the drug and steroid injection.
Mistletoe preparation is an efficient and well tolerated sclerosant agent which needs further investigation.
PMCID: PMC4004388  PMID: 24834119
mistletoe preparation; pleural effusion
8.  A Randomized Study on Postrelapse Disease-Free Survival with Adjuvant Mistletoe versus Oral Etoposide in Osteosarcoma Patients 
Background. Osteosarcoma is a highly malignant bone tumour. After the second relapse, the 12-month postrelapse disease-free survival (PRDFS) rate decreases below 20%. Oral Etoposide is often used in clinical practice after surgery as an “adjuvant” outside any protocol and with only limited evidence of improved survival. Viscum album fermentatum Pini (Viscum) is an extract of mistletoe plants grown on pine trees for subcutaneous (sc) injection with immunomodulatory activity. Methods. Encouraged by preliminary findings, we conducted a study where osteosarcoma patients free from disease after second metastatic relapse were randomly assigned to Viscum sc or Oral Etoposide. Our goal was to compare 12-month PRDFS rates with an equivalent historical control group. Results. Twenty patients have been enrolled, with a median age of 34 years (range 11–65) and a median follow-up time of 38.5 months (3–73). The median PRDSF is currently 4 months (1–47) in the Etoposide and 39 months (2–73) in the Viscum group. Patients getting Viscum reported a higher quality of life due to lower toxicity. Conclusion. Viscum shows promise as adjuvant treatment in prolonging PRDFS after second relapse in osteosarcoma patients. A larger study is required to conclusively determine efficacy and immunomodulatory mechanisms of Viscum therapy in osteosarcoma patients.
PMCID: PMC3988743  PMID: 24803944
9.  Emerging roles of mistletoes in malignancy management 
3 Biotech  2013;4(1):13-20.
Mistletoes are a group of obligate plant semi-parasites in the order Santalales. These clumps of plants growing on a wide range of host plants have been traditionally regarded as medicinal repositories. However, current scientific discoveries have validated their health potentials like never before. Their extracts containing alkaloids, viscotoxins, lectins, and polysaccharides have been evidenced to possess a myriad biological potentials including cancer inhibition. Mistletoes have emerged as promising alternative therapy against colon, oral, lung, and pancreas cancers. The plant extracts bolster immunity, delay tumour initiation and progression, kill malignant tumours, stabilize DNA, alleviate side effects of chemotherapeutics, improve the lifespan, and coping ability of cancer patients and survivors. A range of proprietary formulations viz. Iscador, Eurixor, Helixor, Lektinol, Isorel, Iscucin, Abnoba-viscum and recombinant lectin ML-1 are already being commercialized. This review presents an informative account on the recent developments in mistletoe-mediated cancer management. The underlying mechanisms, possibilities and limitations in cancer therapeutic development are outlined for kindling both researcher and public interest.
PMCID: PMC3909578
Mistletoe; Anticancer; Lectin; Polysaccharide; Immune modifier
10.  Mistletoe treatments for minimising side effects of anticancer chemotherapy 
More than 200,000 persons died in 2002 in Germany as a consequence of cancer diseases. Cancer (ICD-9: 140-208, ICD-10: C00-C97) accounted for 28% of all male deaths and for 22% of all female deaths. Cancer treatment consists on surgery, radio- and chemotherapy. During chemotherapy patients may experience a wide variety of toxic effects (including life-threatening toxicity) which require treatment. The type and the intensity of chemotherapy toxicity are one of the limiting factors in cancer treatment. Toxic effects are also one of the factors affecting health related quality of life (HRQOL) during chemotherapy.
Mistletoe extracts belong to the group of so called „unconventional methods“ and are used in Germany as complementary cancer treatments. It has been postulated that the addition of mistletoe to chemotherapeutical regimes could help reduce chemotherapy-induced toxicity and enhance treatment tolerability.
The German social health insurance covers the prescription of ML I standardized mistletoe extracts when those are prescribed as palliative cancer treatments with the aim of improving HRQOL.
Research questions
Does the addition of mistletoe to chemotherapeutical regimes reduce their toxicity?Does the addition of mistletoe to chemotherapeutical regimes contribute to improve quality of life?Has the addition of mistletoe to chemotherapeutical regimes any effects on survival?Has the addition of mistletoe to chemotherapeutical regimes any effects on tumor-remission?
We conducted a systematic literature search in following databases: The Cochrane Library, DIMDI Superbase and Dissertation Abstracts. We included systematic reviews and randomized controlled trials (RCT). Appraisal of literature was done by two authors independently. Checklists were used to guide literature appraisal. The Jadad-Score was used to score quality of RCT. Evidence was summarized in tables and in narrative form.
Results and discussion
The literature search yielded 437 potentially relevant papers. A total of 94 papers was retrieved. Of them, 48 were potentially relevant for answering the research questions and 46 for background information. In this report we summarize the results from three systematic reviews, five published RCT and two unpublished RCT. A protocol of an ongoing systematic review from the Cochrane Collaboration was also identified.
The information gathered from the systematic reviews was insufficient to answer the research questions. The relevant studies identified and synthetised in these reviews were appraised and extracted again. In addition, a set of recently published RCT was identified and included in these report.
None of the RCT defined frequency or severity of chemotherapy associated toxic effects as its primary outcome. Some of the RCT reported, however, rates of toxic effects or parameters related to toxicity. The results are inconsistent among the RCT ranging from no effect on to positive effects (i. e. reduction) on chemotherapy toxicity. RCT with treatment toxicity as primary outcome are needed to answer the question of whether the addition of mistletoe extracts to chemotherapy regimes can help reducing treatment toxicity.
HRQOL was the primary outcome in four RCT. The addition of mistletoe to chemotherapy showed to have a positive effect on HRQOL of women treated for breast cancer.
The available evidence does not allow giving a conclusive answer to the question of whether the addition of mistletoe to chemotherapeutical regimes can reduce the toxicity of the latter. RCT are needed in which the primary outcome is treatment toxicity. The addition of standardised mistletoe extract to chemotherapeutical regimes in the treatment of women with breast cancer can lead to improvements in HRQOL. In the light of the results from RCT the coverage of mistletoe in cancer treatment should be restricted in Germany to the latter indication.
PMCID: PMC3011359  PMID: 21289969
11.  Triterpenoids Amplify Anti-Tumoral Effects of Mistletoe Extracts on Murine B16.F10 Melanoma In Vivo 
PLoS ONE  2013;8(4):e62168.
Mistletoe extracts are often used in complementary cancer therapy although the efficacy of that therapy is controversially discussed. Approved mistletoe extracts contain mainly water soluble compounds of the mistletoe plant, i.e. mistletoe lectins. However, mistletoe also contains water-insoluble triterpenoids (mainly oleanolic acid) that have anti-tumorigenic effects. To overcome their loss in watery extracts we have solubilized mistletoe triterpenoids with cyclodextrins, thus making them available for in vivo cancer experiments.
Experimental design
B16.F10 subcutaneous melanoma bearing C57BL/6 mice were treated with new mistletoe extracts containing both water soluble compounds and solubilized triterpenoids. Tumor growth and survival was monitored. In addition, histological examinations of the tumor material and tumor surrounding tissue were performed.
Addition of solubilized triterpenoids increased the anti-tumor effects of the mistletoe extracts, resulting in reduced tumor growth and prolonged survival of the mice. Histological examination of the treated tumors showed mainly tumor necrosis and some apoptotic cells with active caspase-3 and TUNEL staining. A significant decrease of CD31-positive tumor blood vessels was observed after treatment with solubilized triterpenoids and different mistletoe extracts.
We conclude that the addition of solubilized mistletoe triterpenoids to conventional mistletoe extracts improves the efficacy of mistletoe treatment and may represent a novel treatment option for malignant melanoma.
PMCID: PMC3629099  PMID: 23614029
12.  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.
PMCID: PMC3135167  PMID: 19939951
13.  Protein Fractions from Korean Mistletoe (Viscum Album coloratum) Extract Induce Insulin Secretion from Pancreatic Beta Cells 
Mistletoe (Viscum Album coloratum) has been known as a medicinal plant in European and Asian countries. Recent data show that biological activity of mistletoe alleviates hypertension, heart disease, renal failure, and cancer development. In this study, we report the antidiabetic effect of Korean mistletoe extract (KME). KME treatments enhanced the insulin secretion from the pancreatic β-cell without any effects of cytotoxicity. PDX-1 and beta2/neuroD known as transcription factors that regulate the expression of insulin gene were upregulated by treatment of the KME protein fractions isolated by ion-exchange chromatography after ammonium sulfate precipitation. Furthermore, these KME protein fractions significantly lowered the blood glucose level and the volume of drinking water in alloxan induced hyperglycemic mice. Taken together with the findings, it provides new insight that KME might be served as a useful source for the development of medicinal reagent to reduce blood glucose level of type I diabetic patients.
PMCID: PMC4053293  PMID: 24959189
14.  Quality of life in patients with gastric cancer: translation and psychometric evaluation of the Iranian version of EORTC QLQ-STO22 
BMC Cancer  2009;9:305.
Disease and treatment related events, can adversely affect the quality of life of patients with cancer. The purpose of this study was to translate and validate a gastric cancer specific health related quality of life questionnaire (EORTC QLQ-STO22) for Iranian patients suffering from gastric cancer.
Forward-backward procedure was applied to translate the English language version of the EORTC QLQ-STO22 into Persian (Iranian language). Then, the questionnaire and the EORTC core quality of life instrument (QLQ-C30) were administered to a sample of patients with confirmed diagnosis of gastric cancer. All patients filled in questionnaires before and after one month of treatment. Patients were divided into two groups based on intension of treatment (curative vs. palliative). Reliability and validity of the module was tested by internal consistency and known group comparisons, respectively.
In all, 105 patients were entered into the study. Cronbach's alpha for multi-item scales (to test reliability) ranged from 0.54 to 0.87. The questionnaire discriminated well between clinically distinct subgroups of patients both before and after treatment lending support to its convergent and clinical validity.
Overall, the Iranian version of the EORTC QLQ-STO22 demonstrated a good reliability and clinical validity to support its use in combination with core questionnaire in outcome studies of gastric cancer in Iran. However, using the QLQ-STO22 in a wide range of Iranian patients with gastric cancer should allow further confirmation for its psychometric properties.
PMCID: PMC2741487  PMID: 19715606
15.  Safety of higher dosages of Viscum album L. in animals and humans - systematic review of immune changes and safety parameters 
Viscum album L extracts (VAE, mistletoe) and isolated mistletoe lectins (ML) have immunostimulating properties and a strong dose-dependent cytotoxic activity. They are frequently used in complementary cancer treatment, mainly to improve quality of life, but partly also to influence tumour growth, especially by injecting VAE locally and in high dosage. The question is raised whether these higher dosages can induce any harm or immunosuppressive effects.
Systematic review of all experiments and clinical studies investigating higher dosages of VAE in animals and humans (Viscum album > 1 mg in humans corresponding to > 0.02 mg/kg in animals or ML > 1 ng/kg) and assessing immune parameters or infections or adverse drug reactions.
69 clinical studies and 48 animal experiments reported application of higher doses of VAE or ML and had assessed immune changes and/or harm. In these studies, Viscum album was applied in dosages up to 1500 mg in humans and 1400 mg/kg in animals, ML was applied up to 6.4 μg/kg in humans and in animals up to 14 μg/kg subcutaneously, 50 μg/kg nasally and 500 μg/kg orally. A variety of immune parameters showed fluctuating or rising outcomes, but no immunosuppressive effect. Side effects consisted mainly of dose-dependent flu-like symptoms (FLS), fever, local reactions at the injection site and various mild unspecific effects. Occasionally, allergic reactions were reported. After application of high doses of recombinant ML, reversible hepatotoxicity was observed in some cases.
Application of higher dosages of VAE or ML is not accompanied by immunosuppression; altogether VAE seems to exhibit low risk but should be monitored by clinicians when applied in high dosages.
PMCID: PMC3180269  PMID: 21871125
16.  Barriers and challenges in integration of anthroposophic medicine in supportive breast cancer care 
SpringerPlus  2013;2:364.
In the last decade, more and more oncology centers are challenged with complementary medicine (CM) integration within supportive breast cancer care. Quality of life (QOL) improvement and attenuation of oncology treatment side effects are the core objectives of integrative CM programs in cancer care. Yet, limited research is available on the use of specific CM modalities in an integrative setting and on cancer patients’ compliance with CM consultation. Studies are especially warranted to view the clinical application of researched CM modalities, such as anthroposophic medicine (AM), a unique CM modality oriented to cancer supportive care. Our objective was to characterize consultation patterns provided by physicians trained in CM following oncology health-care practitioners’ referral of patients receiving chemotherapy. We aimed to identify characteristics of patients who consulted with AM and to explore patients’ compliance to AM treatment. Of the 341 patients consulted with integrative physicians, 138 were diagnosed with breast cancer. Following integrative physician consultation, 56 patients were advised about AM treatment and 285 about other CM modalities. Logistic multivariate regression model found that, compared with patients receiving non-anthroposophic CM, the AM group had significantly greater rates of previous CM use [EXP(B) = 3.25, 95% C.I. 1.64-6.29, p = 0.001] and higher rates of cancer recurrence at baseline (p = 0.038). Most AM users (71.4%) used a single AM modality, such as mistletoe (viscum album) injections, oral AM supplements, or music therapy. Compliance with AM modalities following physician recommendation ranged from 44% to 71% of patients. We conclude that AM treatment provided within the integrative oncology setting is feasible based on compliance assessment. Other studies are warranted to explore the effectiveness of AM in improving patients’ QOL during chemotherapy.
PMCID: PMC3736081  PMID: 23961426
Integrative medicine; Anthroposophic medicine; Viscum album; Quality of life; Complementary medicine; Cancer
17.  Viscum album L. extracts in breast and gynaecological cancers: a systematic review of clinical and preclinical research 
Viscum album L. extracts (VAE, European mistletoe) are a widely used medicinal plant extract in gynaecological and breast-cancer treatment.
Systematic review to evaluate clinical studies and preclinical research on the therapeutic effectiveness and biological effects of VAE on gynaecological and breast cancer. Search of databases, reference lists and expert consultations. Criteria-based assessment of methodological study quality.
19 randomized (RCT), 16 non-randomized (non-RCT) controlled studies, and 11 single-arm cohort studies were identified that investigated VAE treatment of breast or gynaecological cancer. They included 2420, 6399 and 1130 patients respectively. 8 RCTs and 8 non-RCTs were embedded in the same large epidemiological cohort study. 9 RCTs and 13 non-RCTs assessed survival; 12 reported a statistically significant benefit, the others either a trend or no difference. 3 RCTs and 6 non-RCTs assessed tumour behaviour (remission or time to relapse); 3 reported statistically significant benefit, the others either a trend, no difference or mixed results. Quality of life (QoL) and tolerability of chemotherapy, radiotherapy or surgery was assessed in 15 RCTs and 9 non-RCTs. 21 reported a statistically significant positive result, the others either a trend, no difference, or mixed results. Methodological quality of the studies differed substantially; some had major limitations, especially RCTs on survival and tumour behaviour had very small sample sizes. Some recent studies, however, especially on QoL were reasonably well conducted. Single-arm cohort studies investigated tumour behaviour, QoL, pharmacokinetics and safety of VAE. Tumour remission was observed after high dosage and local application. VAE application was well tolerated. 34 animal experiments investigated VAE and isolated or recombinant compounds in various breast and gynaecological cancer models in mice and rats. VAE showed increase of survival and tumour remission especially in mice, while application in rats as well as application of VAE compounds had mixed results. In vitro VAE and its compounds have strong cytotoxic effects on cancer cells.
VAE shows some positive effects in breast and gynaecological cancer. More research into clinical efficacy is warranted.
PMCID: PMC2711058  PMID: 19519890
18.  Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review 
BMC Cancer  2009;9:451.
In Europe, extracts from Viscum album (VA-E), the European white-berry mistletoe, are widely used to treat patients with cancer.
We searched several databases such as Cochrane, EMBASE, NCCAM, NLM, DIMDI, CAMbase, and Medline. Inclusion criteria were controlled clinical studies on parameters associated with survival in cancer patients treated with Iscador. Outcome data were extracted as they were given in the publication, and expressed as hazard ratios (HR), their logarithm, and the respective standard errors using standard formulas.
We found 49 publications on the clinical effects of Iscador usage on survival of cancer patients which met our criteria. Among them, 41 studies and strata provided enough data to extract hazard ratios (HR) and their standard errors (Iscador versus no extra treatment). The majority of studies reported positive effects in favour of the Iscador application. Heterogeneity of study results was moderate (I2 = 38.3%, p < 0.0001). The funnel plots were considerably skewed, indicating a publication bias, a notion which is corroborated by statistical means (AC = -1.3, CI: -1.9 to -0.6, p <= 0.0001). A random effect meta-analysis estimated the overall hazard ratio at HR = 0.59 (CI: 0.53 to 0.66, p < 0.0001). Randomized studies showed less effects than non-randomized studies (ratio of HRs: 1.24, CI: 0.79 to 1.92, p = 0.35), and matched-pair studies gave significantly better results than others (ratio of HRs: 0.33; CI: 0.17 to 0.65, p = 0.0012).
Pooled analysis of clinical studies suggests that adjuvant treatment of cancer patients with the mistletoe extract Iscador is associated with a better survival. Despite obvious limitations, and strong hints for a publication bias which limits the evidence found in this meta-analysis, one can not ignore the fact that studies with positive effects of VA-E on survival of cancer patients are accumulating. Future studies evaluating the effects of Iscador should focus on a transparent design and description of endpoints in order to provide greater insight into a treatment often being depreciated as ineffective, but highly valued by cancer patients.
PMCID: PMC2804713  PMID: 20021637
19.  Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—Part 1 
Current Oncology  2006;13(1):14-26.
An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways that support tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibit tumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose–response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies.
PMCID: PMC1891166  PMID: 17576437
Angiogenesis; anti-angiogenic; natural health products; herbal medicine; anticancer; clinical trials; integrative; molecular biology
20.  Fermented Mistletoe Extract as a Multimodal Antitumoral Agent in Gliomas 
In Europe, commercially available extracts from the white-berry mistletoe (Viscum album L.) are widely used as a complementary cancer therapy. Mistletoe lectins have been identified as main active components and exhibit cytotoxic effects as well as immunomodulatory activity. Since it is still not elucidated in detail how mistle toe extracts such as ISCADOR communicate their effects, we analyzed the mechanisms that might be responsible for their antitumoral function on a molecular and functional level. ISCADOR-treated glioblastoma (GBM) cells down-regulate central genes involved in glioblastoma progression and malignancy such as the cytokine TGF-β and matrix-metalloproteinases. Using in vitro glioblastoma/immune cell co-cultivation assays as well as measurement of cell migration and invasion, we could demonstrate that in glioblastoma cells, lectin-rich ISCADOR M and ISCADOR Q significantly enforce NK-cell-mediated GBM cell lysis. Beside its immune stimulatory effect, ISCADOR reduces the migratory and invasive potential of glioblastoma cells. In a syngeneic as well as in a xenograft glioblastoma mouse model, both pretreatment of tumor cells and intratumoral therapy of subcutaneously growing glioblastoma cells with ISCADOR Q showed delayed tumor growth. In conclusion, ISCADOR Q, showing multiple positive effects in the treatment of glioblastoma, may be a candidate for concomitant treatment of this cancer.
PMCID: PMC3485514  PMID: 23133496
21.  Adverse Drug Reactions and Expected Effects to Therapy with Subcutaneous Mistletoe Extracts (Viscum album L.) in Cancer Patients 
Background. In Europe, mistletoe extracts are widely used as a complementary cancer therapy. We assessed the safety of subcutaneous mistletoe as a conjunctive therapy in cancer patients within an anthroposophic medicine setting in Germany. Methods. A multicentre, observational study was performed within the Network Oncology. Suspected mistletoe adverse drug reactions (ADRs) were described by frequency, causality, severity, and seriousness. Potential risk factors, dose relationships and drug-drug interactions were investigated. Results. Of 1923 cancer patients treated with subcutaneous mistletoe extracts, 283 patients (14.7%) reported 427 expected effects (local reactions <5 cm and increased body temperature <38°C). ADRs were documented in 162 (8.4%) patients who reported a total of 264 events. ADRs were mild (50.8%), moderate (45.1%), or severe (4.2%). All were nonserious. Logistic regression analysis revealed that expected effects were more common in females, while immunoreactivity decreased with increasing age and tumour stage. No risk factors were identified for ADRs. ADR frequency increased as mistletoe dose increased, while fewer ADRs occurred during mistletoe therapy received concurrent with conventional therapies. Conclusion. The results of this study indicate that mistletoe therapy is safe. ADRs were mostly mild to moderate in intensity and appear to be dose-related and explained by the immune-stimulating, pharmacological activity of mistletoe.
PMCID: PMC3929984  PMID: 24672577
22.  Evaluation of Preclinical Assays to Investigate an Anthroposophic Pharmaceutical Process Applied to Mistletoe (Viscum album L.) Extracts 
Extracts from European mistletoe (Viscum album L.) developed in anthroposophic medicine are based on specific pharmaceutical procedures to enhance remedy efficacy. One such anthroposophic pharmaceutical process was evaluated regarding effects on cancer cell toxicity in vitro and on colchicine tumor formation in Lepidium sativum. Anthroposophically processed Viscum album extract (APVAE) was produced by mixing winter and summer mistletoe extracts in the edge of a high-speed rotating disk and was compared with manually mixed Viscum album extract (VAE). The antiproliferative effect of VAE/APVAE was determined in five cell lines (NCI-H460, DU-145, HCC1143, MV3, and PA-TU-8902) by WST-1 assay in vitro; no difference was found between VAE and APVAE in any cell line tested (P > 0.14). Incidence of colchicine tumor formation was assessed by measurement of the root/shoot-ratio of seedlings of Lepidium sativum treated with colchicine as well as VAE, APVAE, or water. Colchicine tumor formation decreased after application of VAE (−5.4% compared to water, P < 0.001) and was even stronger by APVAE (−8.8% compared to water, P < 0.001). The high-speed mistletoe extract mixing process investigated thus did not influence toxicity against cancer cells but seemed to sustain morphostasis and to enhance resistance against external noxious influences leading to phenomenological malformations.
PMCID: PMC4024402  PMID: 24876872
23.  Durable Regression of Primary Cutaneous B-Cell Lymphoma Following Fever-inducing Mistletoe Treatment: Two Case Reports 
Background: Mistletoe is a complementary cancer treatment that is widely used, usually in addition to and alongside recommended conventional cancer therapy. However, little is known about its use, effectiveness, and safety in the treatment of cutaneous lymphoma.
Case Report: Two patients with primary cutaneous B-cell lymphoma (pT2bcNxM0 follicle center and pT2ac-NxM0 marginal zone) either declined or postponed recommended conventional treatment and received high-dose, fever-inducing mistletoe treatment; a combination of intratumoral, subcutaneous, and intravenous application was given; and one patient also underwent whole-body hyperthermia. The lymphoma regressed over a period of 12 and 8 months, respectively, and after administration of a cumulative dose of 12.98 g and 4.63 g mistletoe extract, respectively. The patients are in remission to date, 3.5 years after commencement of treatment. Neither patient received conventional cancer treatment during the entire observation period.
PMCID: PMC3833476  PMID: 24278797
Mistletoe treatment; Lymphoma; primary cutaneous B-cell lymphoma; fever; PCBCL; PCFCL; PCMZL; cancer; tumor
24.  Preclinical and Clinical Effects of Mistletoe against Breast Cancer 
BioMed Research International  2014;2014:785479.
Breast cancer is among the most frequent types of cancer in women worldwide. Current conventional treatment options are accompanied by side effects. Mistletoe is amongst the important herbal medicines traditionally used as complementary remedies. An increasing number of studies have reported anticancer activity of mistletoe extracts on breast cancer cells and animal models. Some recent evidence suggests that cytotoxic activity of mistletoe may be mediated through different mechanisms. These findings provide a good base for clinical trials. Various studies on mistletoe therapy for breast cancer patients revealed similar findings concerning possible benefits on survival time, health-related quality of life (HRQoL), remission rate, and alleviating adverse reactions to conventional therapy. This review provides an overview of the recent findings on preclinical experiments and clinical trials of mistletoe for its cytotoxic and antitumor activity and its effect on HRQoL in breast cancer patients. Moreover, studies investigating molecular and cellular mechanisms underlying antitumor activity of mistletoe are discussed in this paper. The analyzed trials provided evidence that there might be a combination of pharmacological and motivational aspects mediated by the mistletoe extract application which may contribute to the clinical benefit and positive outcome such as improved HRQoL and self-regulation in breast cancer patients.
PMCID: PMC4127267  PMID: 25136622
25.  Induction of apoptosis of endothelial cells by Viscum album: a role for anti-tumoral properties of mistletoe lectins. 
Molecular Medicine  2002;8(10):600-606.
BACKGROUND: Viscum album (VA) preparations consist of aqueous extracts of different types of lectins of VA. Mistletoe lectins have both cytotoxic and immunomodulatory properties that support their study for the development for cancer therapy. However, the mechanisms of the anti- tumoral properties in vivo of mistletoe lectins are not fully understood. Because endothelial cells (EC) play a pivotal role in tumor angiogenesis, we tested the hypothesis that VA extracts induce endothelial cell death and apoptosis. MATERIALS AND METHODS: We investigated the effect of various VA preparations on both human venous endothelial cell (HUVEC) and immortalized human venous endothelial cell line (IVEC) using morphologic assessment of EC, FACScan analysis after propidium iodine and annexin V labeling, and detection of cleavage of poly(A)DP-ribose polymerase (PARP). RESULTS: All tested VA preparations, except Iscador P, were cytotoxic in IVEC. Apoptosis, assessed by morphologic examination, annexin V labeling, and Western blot analysis for PARP cleavage, was involved in HUVEC cell death induced by VA preparations derived from plants that grow on oak trees (VA Qu FrF). CONCLUSIONS: Results from the present study suggest that VA extract-induced endothelial apoptosis may explain the tumor regression associated with the therapeutic use of VA preparations and support further investigations to develop novel anti-angiogenic compounds based on mistletoe compounds.
PMCID: PMC2039938  PMID: 12477970

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