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Oncopharmacological Perspectives of a Plant Lectin (Viscum album Agglutinin-I): Overview of Recent Results from In vitro Experiments and In vivo Animal Models, and Their Possible Relevance for Clinical Applications.

Hajtó T, Hostanska K, Berki T, Pálinkás L, Boldizsár F, Németh P - Evid Based Complement Alternat Med (2005)

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Mistletoe extracts were applied to a large number of cancer patients because of their modulatory effect on the natural immune system... By carefully removing lectins, an essential group of components, from mistletoe extracts, a significant reduction of their effectiveness on several cellular immune parameters could be observed in vivo... Meanwhile, the quantitatively dominant lectin, Viscum album agglutinin (VAA)-I has become available in a recombinant form (rVAA)... Other constitiuents of plant extracts such as viscotoxins, poly- and oligosaccharides, flavonoids, chitin-binding mistletoe lectin and arginine have also been investigated in connection with the effects of mistletoe extracts on the host defense... However, little evidence has been found that these substances contribute to the effects of mistletoe in vivo... The recombinant VAA (rVAA) showed similar biological activity [cytotoxicity, RIP activity, induction of apoptosis, selective binding, release of cytokines and stimulation of natural killer (NK) function] to that found in the plant extract (VAA-I)... In a skin model system, VAA-I (0.75–8 ng/ml) given in isolated form or in mistletoe extracts caused increased release of IL-1α and IL-6 dose dependently... In a model of multilayered keratinocytes, similar results were found... With regard to cellular immunological reactions in vivo, a bell-shaped dose–response curve of VAA-I and mistletoe extract could be observed (Fig. 4)... A single injection of pure VAA-I (0.25–1 ng/kg) into rabbits dose dependently enhances their temperature as well as the number and phagocytitic activity of granulocytes, the cytotoxic activity of NK cells and the number of large granular lymphocytes (LGLs) in peripheral blood... The maximum effect was found at 0.8 ng/kg body weight... Experiments with mistletoe extracts standardized with regard to lectin activity suggest that an immunological stimulation induced by an optimal lectin dose (1 ng VAA-I/kg) can only be repeated after 3 days without therapy... In rats, recombinant mistletoe lectin (rVAA) also showed a bell-shaped dose–response relationship when the activity and frequency of NK cells in the blood were investigated after a single injection of various doses (Fig. 4) Similar results were published recently with Argentine mistletoe Ligaria cuneifolia applied in a murine model... The priming of the granulocytes was tested 5 h after the injections... In both studies, a significant increase in the priming of granulocytes 5 h after the injection of purified VAA-I was found as compared with placebo controls (Table 1).

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Cytokine gene expression in cultured PBMCs (31). After 24 h of culture in the absence (lane 1) and in the presence of 10 ng/ml (lane 2) or 1 ng/ml (lane 3) VAA-I and 1.5 μg/ml PHA (lane 4), total cellular RNA was extracted, reverse-transcribed and assayed in 35 cycles of PCR in the presence of the indicated pairs of primers. (The figure was kindly provided by S. Karger AG, Switzerland.)
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fig2: Cytokine gene expression in cultured PBMCs (31). After 24 h of culture in the absence (lane 1) and in the presence of 10 ng/ml (lane 2) or 1 ng/ml (lane 3) VAA-I and 1.5 μg/ml PHA (lane 4), total cellular RNA was extracted, reverse-transcribed and assayed in 35 cycles of PCR in the presence of the indicated pairs of primers. (The figure was kindly provided by S. Karger AG, Switzerland.)

Mentions: The results of cytokine research with regard to mistletoe are almost exclusively from in vitro data that cannot be directly transferred to in vivo situations. In vivo, cytokines are active at very low concentrations in a complex network. In vitro and in vivo, effective immunomodulators can only bring about short-term changes in serum concentrations of cytokines and only to a very small degree (picogram range) (30). The investigation of lectin-induced proinflammatory cytokines was also important because cancer patients often show decreased inflammatory responsiveness. In 24 h culture of PBMCs, low and non-toxic lectin concentrations (with an optimum between 1 and 10 ng/ml) stimulate the release of proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α dose dependently. d-Galactose, a monosaccharide with the highest affinity for VAA-I, blocks TNF-α release competitively. Mannose that shows no affinity for VAA-I has no effect in comparable concentrations. These results confirm that sugar–protein interaction mediated by the sugar-binding B-chain is fundamental for the immunomodulating effect of VAA-I. An enhanced expression of TNF-α mRNA was induced in human monocytes and in macrophages from endotoxin-resistant (C3H/HeJ) mice, if these cells had been pre-incubated with VAA-I for 2 h (40). After 24 h incubation of human PBMCs with non-cytotoxic concentrations of VAA-I (10 and 1 ng/ml), the expression of mRNA was measured for a series of cytokines with the help of reverse polymerase chain reaction (rPCR) (31) (Fig. 2). VAA-I induced gene expression of IL-1α and β, IL-6, TNF-α, interferon (IFN)-γ, granulocyte–monocyte colony-stimulating factor (GM-CSF) and IL-10. In contrast, no expression of IL-2 and IL-5 could be found. Non-cytotoxic concentrations of other mistletoe lectins (II and III) also induced increased secretion of proinflammatory cytokines in monocytes isolated from peripheral blood (41).


Oncopharmacological Perspectives of a Plant Lectin (Viscum album Agglutinin-I): Overview of Recent Results from In vitro Experiments and In vivo Animal Models, and Their Possible Relevance for Clinical Applications.

Hajtó T, Hostanska K, Berki T, Pálinkás L, Boldizsár F, Németh P - Evid Based Complement Alternat Med (2005)

Cytokine gene expression in cultured PBMCs (31). After 24 h of culture in the absence (lane 1) and in the presence of 10 ng/ml (lane 2) or 1 ng/ml (lane 3) VAA-I and 1.5 μg/ml PHA (lane 4), total cellular RNA was extracted, reverse-transcribed and assayed in 35 cycles of PCR in the presence of the indicated pairs of primers. (The figure was kindly provided by S. Karger AG, Switzerland.)
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Related In: Results  -  Collection

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fig2: Cytokine gene expression in cultured PBMCs (31). After 24 h of culture in the absence (lane 1) and in the presence of 10 ng/ml (lane 2) or 1 ng/ml (lane 3) VAA-I and 1.5 μg/ml PHA (lane 4), total cellular RNA was extracted, reverse-transcribed and assayed in 35 cycles of PCR in the presence of the indicated pairs of primers. (The figure was kindly provided by S. Karger AG, Switzerland.)
Mentions: The results of cytokine research with regard to mistletoe are almost exclusively from in vitro data that cannot be directly transferred to in vivo situations. In vivo, cytokines are active at very low concentrations in a complex network. In vitro and in vivo, effective immunomodulators can only bring about short-term changes in serum concentrations of cytokines and only to a very small degree (picogram range) (30). The investigation of lectin-induced proinflammatory cytokines was also important because cancer patients often show decreased inflammatory responsiveness. In 24 h culture of PBMCs, low and non-toxic lectin concentrations (with an optimum between 1 and 10 ng/ml) stimulate the release of proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α dose dependently. d-Galactose, a monosaccharide with the highest affinity for VAA-I, blocks TNF-α release competitively. Mannose that shows no affinity for VAA-I has no effect in comparable concentrations. These results confirm that sugar–protein interaction mediated by the sugar-binding B-chain is fundamental for the immunomodulating effect of VAA-I. An enhanced expression of TNF-α mRNA was induced in human monocytes and in macrophages from endotoxin-resistant (C3H/HeJ) mice, if these cells had been pre-incubated with VAA-I for 2 h (40). After 24 h incubation of human PBMCs with non-cytotoxic concentrations of VAA-I (10 and 1 ng/ml), the expression of mRNA was measured for a series of cytokines with the help of reverse polymerase chain reaction (rPCR) (31) (Fig. 2). VAA-I induced gene expression of IL-1α and β, IL-6, TNF-α, interferon (IFN)-γ, granulocyte–monocyte colony-stimulating factor (GM-CSF) and IL-10. In contrast, no expression of IL-2 and IL-5 could be found. Non-cytotoxic concentrations of other mistletoe lectins (II and III) also induced increased secretion of proinflammatory cytokines in monocytes isolated from peripheral blood (41).

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Mistletoe extracts were applied to a large number of cancer patients because of their modulatory effect on the natural immune system... By carefully removing lectins, an essential group of components, from mistletoe extracts, a significant reduction of their effectiveness on several cellular immune parameters could be observed in vivo... Meanwhile, the quantitatively dominant lectin, Viscum album agglutinin (VAA)-I has become available in a recombinant form (rVAA)... Other constitiuents of plant extracts such as viscotoxins, poly- and oligosaccharides, flavonoids, chitin-binding mistletoe lectin and arginine have also been investigated in connection with the effects of mistletoe extracts on the host defense... However, little evidence has been found that these substances contribute to the effects of mistletoe in vivo... The recombinant VAA (rVAA) showed similar biological activity [cytotoxicity, RIP activity, induction of apoptosis, selective binding, release of cytokines and stimulation of natural killer (NK) function] to that found in the plant extract (VAA-I)... In a skin model system, VAA-I (0.75–8 ng/ml) given in isolated form or in mistletoe extracts caused increased release of IL-1α and IL-6 dose dependently... In a model of multilayered keratinocytes, similar results were found... With regard to cellular immunological reactions in vivo, a bell-shaped dose–response curve of VAA-I and mistletoe extract could be observed (Fig. 4)... A single injection of pure VAA-I (0.25–1 ng/kg) into rabbits dose dependently enhances their temperature as well as the number and phagocytitic activity of granulocytes, the cytotoxic activity of NK cells and the number of large granular lymphocytes (LGLs) in peripheral blood... The maximum effect was found at 0.8 ng/kg body weight... Experiments with mistletoe extracts standardized with regard to lectin activity suggest that an immunological stimulation induced by an optimal lectin dose (1 ng VAA-I/kg) can only be repeated after 3 days without therapy... In rats, recombinant mistletoe lectin (rVAA) also showed a bell-shaped dose–response relationship when the activity and frequency of NK cells in the blood were investigated after a single injection of various doses (Fig. 4) Similar results were published recently with Argentine mistletoe Ligaria cuneifolia applied in a murine model... The priming of the granulocytes was tested 5 h after the injections... In both studies, a significant increase in the priming of granulocytes 5 h after the injection of purified VAA-I was found as compared with placebo controls (Table 1).

No MeSH data available.


Related in: MedlinePlus