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

Abstract

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.

Safety of Combined Treatment With Monoclonal Antibodies and Viscum album L Preparations

“…12,13 Furthermore, it has been suggested that VA preparations can induce clinically beneficial immunomodulation through lectin-carbohydrate interactions, leading to enhancement of interleukin-12 secretion and natural killer cell function. 14,15 Therefore, use of VA therapy preparations alongside mAb might help improve the balance of the innate immune system, thereby decreasing treatment-related toxicities and possibly even helping in overcoming tumor-induced immunosuppression and treatment resistance. Whereas at least 1 group has thoroughly investigated the safety of combined use of VA preparations and the chemotherapeutic agent, gemcitabine, 16 we were unable to find information regarding the safety of combined use of VA preparations and mAb.…”

Intratumoral Mistletoe (Viscum album L) Therapy in Patients With Unresectable Pancreas Carcinoma

“…In German-speaking countries, there is a high prevalence of complementary and alternative medicine, 41,42 and European mistletoe extracts (Viscum album L.) are the mostly frequently prescribed herbal remedies. [43][44][45][46][47][48] An overview on the mode of action of mistletoe extracts is given by Bar-Sela 49 and has been well summarized by Zänker et al 50 In vitro, it showed antitumoral effects, such as induction of apoptosis, [44][45][46][47][48]51 inhibition of cell proliferation, 47,48,52 potentiating anticancer effects of TNF-alpha, 53,54 activation of immunocompetent cells, [54][55][56][57] decreasing angiogenesis, 50,53 and retention of chemotherapeutic agents in cancer cells by modulating the transport of cell-toxifying substances. 58 Whereas systemic mistletoe therapy primary aims to stimulate the immune system, intratumoral application focuses on the local cytotoxic effect.…”

Production of Active Nonglycosylated Recombinant B‐Chain of Type‐2 Ribosome‐Inactivating Protein from Viscum articulatum and Its Biological Effects on Peripheral Blood Mononuclear Cells

“…Experiments in animal models suggest that ML-I-mediated inhibition of tumor growth is associated with immunomodulatory efficacy [ 20 ]. In a Scid mouse xenograft model, Thies et al recently reported low-dose ML-I reducing melanoma growth and number of metastasis primarily due to its immunomodulatory effects, while higher dose lost this effect.…”