Mistel

Erstellt am 29 Jun 2018 17:45
Zuletzt geändert: 03 Sep 2022 02:52

Systematische Übersichten

As already mentioned, not only lectins but also other components such as viscotoxins, Kuttan peptide, polysaccharides and vesicles have been suggested by several authors for participating in the immunomodulatory efficacy of ME.
The removal of mistletoe lectins (MLs) from the immunologically effective mistletoe extract (ME) resulted in immunosuppressive responses in healthy volunteers injected with the lectin-free preparation. This residual immunotoxicity of lectin-free extracts may be related to viscotoxins, which can cytolytically damage cell membranes; other components, such as viscin may also be involved.
However, an exact summary of the results obtained with ME in human cancer therapy is not possible because the application of ME is rather heterogeneous and in many cases not reproducible. In addition, without appropriate standardization, ME and ML may induce immunological side effects, as it was found after high lectin doses in several cellular immune parameters were tested.
MEs in high and non-optimal doses can induce more side effects because apart from the toxic effect of overdosed ML, other toxic substances (such as viscotoxins and viscin) can also be involved.

RESULTS:
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), …
CONCLUSIONS:
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.

andere Übersichten

ältere Übersichten

  • Edler L. Chemotherapie mit komplementärer Misteltherapie: wie evident ist ihre Wirksamkeit wirklich? Internist Praxis. 2003;43:895-904.

Based on literature data, immunomodulation by the lectin involves enhanced secretion of multifunctional proinflammatory cytokines such as IL-6. The apparently context-dependent ambivalence of their actions includes capacity to serve as autocrine and paracrine tumor growth and survival factors for a wide variety of tumor cell types in vitro and in vivo, as illustrated by the literature presented. The potential for clinical risks is indicated to be non-negligible, e.g. for lymphomas, advanced-stage melanomas and renal cell carcinomas. Moreover, negative effects of immunomodulatory lectin or extract treatment have already been reported. To reliably prove clinical efficacy and exclude lack of undesired side effects for each tumor class and stage, it is mandatory to evaluate the performance of this experimental therapy modality exclusively in relevant preclinical settings and strictly controlled clinical studies to obey the generally accepted rule: primum non nocere.

Positive Fallberichte

  • Kim DK, Kim BR, Jeong JS, Baek YH. Analysis of intrahepatic sarcomatoid cholangiocarcinoma: Experience from 11 cases within 17 years. World J Gastroenterol. 2019;25(5):608-621. doi:10.3748/wjg.v25.i5.608.

Von 11 Patienten überlebte einer mehr als 1 Jahr. Dieser hatte den kleinsten Tumor und wurde nur mit Mistel behandelt. Durchschnittsüberleben war unter 150 Tagen.

Negativ-Studien

Results: Raw data analysis of an additional ML-I treatment yielded a worse outcome (p=0.02) for patients with ML treatment, possibly due to a bias inherent in the ML-I-treated patients. Using the "similar case" method (a case-based reasoning approach) we could not confirm this harm for patients using ML-I. Analysis of life quality data did not demonstrate reliable differences between patients treated with ML-I treatment and those without proven ML-I treatment.

  • Eggermont AMM, Kleeberg UR, Ruiter DJ, and Suciu S: European Organization for Research and Treatment of Cancer Melanoma Group. Trial experience with more than 2,000 patients, evaluating adjuvant treatment with low or intermediate doses of interferon alpha-2b. In: Perry MC: American Society of Clinical Oncology. Educational Book, 2001; 37th Annual Meeting. Alexandria, VA, USA, 88–93.

Dieser Bericht über das Ergebnis einer EORTC/DKG-Studie an Melanompatienten dokumentiert, dass die Behandlung mit einem Mistelpräparat bei Patienten mit positiven Lymphknoten die Zeit des krankheitsfreien Intervalls und die Gesamtüberlebenszeit senkte und die Häufigkeit von Hirnmetastasen erhöhte. In der Publikation lautete die Schlussfolgerung der Autoren: "treatment with Iscador may accelerate and alter the course of the disease"..

Diskussion im Deutschen Ärzteblatt 2004

Studien, Fallberichte mit Gefahrensignal

Es wurden Leukämie-Zellen untersucht:
Additionally, tested remedies stimulated survival of leukemic cells in 45%, 96%, and 83% cases, respectively; while no effect was observed in normal lymphocytes. In combination studies, Viscum album extract did not increase prednisolone and cytarabine cytotoxicity in leukemic cells.

Aviscumine stimulated the immune system with a release of cytokines such as interleukin (IL)-1beta, IL-6 and interferon-gamma, and induced immunoglobulin (Ig) G- and/or IgM-anti-aviscumine antibodies of uncertain clinical relevance.

In dieser Studie ergaben sich für Viscum Album (Iscador®) Hinweise auf beschleunigtes Tumorwachstum. Aufgrund dieses Ergebnisses wird in aktuellen Leitlinien (auch noch im Jahr 2018) von einer adjuvanten Mistelbehandlung bei Melanom-Patienten abgeraten.

A galactoside-specific lectin from Viscum album L. (VAA) has been reported to induce certain lymphokines and upregulate IL-2 receptors on lymphocytes. Present study was, therefore, designed to compare the effects of combination therapy with IL-2 (10(4) Cetus units/mouse, intraperitoneal (i.p). every 8 h, given as 5 day rounds per week, for one or two rounds) and VAA (1 ng/kg subcutaneous (s.c.), biweekly) with those of IL-2 or VAA therapy alone in C3H/HeJ female mice bearing s.c. transplants of a highly metastatic C3L5 mammary adenocarcinoma. IL-2 therapy alone reduced tumour growth and metastasis, but caused significant water retention indicative of capillary leakage in the kidneys after both rounds of therapy, whereas pleural effusion was only evident after the first round and not the second round. A sharp rise in the systemic NO levels after the first round, followed by a decline after the second round of IL-2 therapy suggested a causal relationship of increased NO levels to pleural effusion. A strong immunostaining for nitrotyrosine (a marker for the production of peroxynitrite) was noted in the renal tubules at the end of both rounds of therapy suggestive of a causal association of this toxic NO-metabolite with capillary leakage in the kidneys. Addition of VAA to IL-2 therapy had no effect on any of the above parameters. Unexpectedly, however, VAA therapy alone stimulated tumour growth as well as lung metastases. NO induction in the C3L5 cells by VAA was excluded as a possible reason for this stimulation. Present results suggest the need for exercising caution in the use of VAA as an immunoadjuvant in human cancer therapy.

Leserbrief als Antwort auf den Artikel: Beeinflusst die Misteltherapie die Abwehr epithelialer Tumoren? Dtsch Med Wochenschr 2001; 126(49): 1416-1416; DOI: 10.1055/s-2001-42876:
»Unabhängig von der Verordnungsfähigkeit zu Lasten der Gesetzlichen Krankenversicherung erscheint uns in Anbetracht der wissenschaftlichen Datenlage die Nutzen-Risiko-Bilanz für Krebspatienten negativ«. Zu diesem Urteil über die Anwendung von Mistelextrakten kommt das unabhängige arznei-telegramm (Heft 9/1999, S. 94) im Gegensatz zu den Autoren der Übersichtsarbeit in dieser Wochenschrift [8]. Warum wir diese in der DMW erschienene Übersicht für nicht ausgewogen halten, soll folgende kurzgefasste Auflistung aufzeigen:
1. Der geweckte Eindruck einer eindeutig positiven Korrelation von Immunparametern zu effektiver Tumorabwehr irritiert. In dieses Konzept lassen sich u. a. tumorfördernde Wirkungen von Immunfaktoren und Absinken der Inzidenz des Mammakarzinoms in Verbindung mit transplantationsbedingter Immunsuppression nicht einfügen (Literatur in [2-4]). Kritische Sichtung der Literatur unterstreicht, dass solche Darstellungen dazu dienen können, »unberechtigte Hoffnungen zu wecken« [6].
[…]
4. Während der Drucklegung der o. g. Übersicht sind zwei Artikel publiziert, die für die besprochene Problematik und aktuelle Diskussion von Interesse sind: fehlender Einfluss der Mistelbehandlung auf die Lebensqualität in einer kontrollierten klinischen Studie [7] und Nachweis der Stimulation menschlicher Tumorzellen (Linien und Explantate) durch Lektinbehandlung im klinisch empfohlenen Niedrigdosisbereich…

Aus dem Abstrakt:
VAA-I allein hatte keinen messbaren Effekt auf das klonogene Wachstum der isolierten Zellen. Bei Konzentrationen von 100 und 250 pg/ml erhöhte VAA-I jedoch die Zytokin-abhängige Proliferation und Differenzierung von CD34+ Zellen um einen Median von 75 bzw. 85%. Die Ergebnisse zeigen, dass VAA-I an hämatopoetische Vorläuferzellen bindet und einen ko-stimulierenden Effekt auf deren Proliferation hat.

Selten und nicht Mistel-spezifisch: Anaphylaxie

NB: Anaphylaktische Reaktionen kommen bei Immuntherapien mit Checkpoint-Blockern oder bei monoklonalen Antikörpern ebenfalls vor; vermutlich sogar häufiger. Der Einzelfall wurde hier nur der Vollständigkeit halber aufgenommen.

Zytokine, IL-6

The viability of PD-MSCs was significantly enhanced up to 1.5-fold in the 10 pg/mL VCA-treated group compared to the untreated group (p < 0.05); moreover, cell viability of PD-MSCs was significantly decreased in the groups treated with 5000 and 10,000 pg/mL VCA compared with the no treatment group. Similar to PD-MSCs, the viability of BM-MSCS was significantly enhanced at a low concentration of VCA (5 pg/mL) and decreased at 10,000 pg/mL VCA compared with no treatment (p < 0.05). … Oct4 and Sox2 mRNA expression was significantly increased in PD-MSCs treated with VCA (10 pg/mL) up to 4.4-and 2.7-fold compared with untreated PD-MSCs (p < 0.05). These findings suggest that a low concentration of VCA increases the proliferation of MSCs but that a high concentration of VCA decreases it. The increased proliferation of MSCs at the low VCA concentration appears to be affected by upregulation of stemness-related markers, such as Oct4, Sox2 and Nanog.
mRNA expression of IL-6 was significantly increased up to 3~4-fold in PD-MSCs treated with VCA (10 and 100 pg/mL) compared with untreated PD-MSCs (p < 0.05). IL-6 activity in PD-MSCs was significantly increased with 1 pg/mL VCA compared with no treatment (p < 0.05). In the case of BM-MSCs, expression of IL-6 was significantly increased by 1.2-fold in the 5 pg/mL VCA-treated group compared with the untreated group (p < 0.05) … but not … at all concentratons … results indicate that VCA may enhance the proliferation of MSCs through epigenetic regulation of IL-6/STAT3.
We confirmed that VCA enhances the self-renewal activity of PD-MSCs via increased expression of IL-6.
To our knowledge, we are the first to demonstrate that low concentrations of VCA directly regulate methylation of the genes encoding the proinflammatory cytokines IL-6 and STAT3.

We previously isolated a lectin (ML-J) from Japanese mistletoe. In the present study, we examined the effects of ML-J on cytokine gene expression in human colon adenocarcinoma Caco-2 cells and in the mouse intestine. The results of reverse transcription-polymerase chain reaction and quantitative real-time polymerase chain reaction indicated that ML-J caused an upregulation of the gene expression of the proinflammatory cytokines interleukin (IL)-8, tumor necrosis factor-alpha (TNF-alpha) and IL-6 in Caco-2 cells and TNF-alpha and IL-6 in the duodenum. This study provides the first example to show that a perorally administered plant lectin affects gene expression in the duodenum.

Hintergrund: Bedeutung von Interleukin-6

Hintergrund: Geschichte der Mistel als onkologisches Therapeutikum

Sonstiges - WebLinks

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