Evidence for Stimulation of Tumor Proliferation in Cell Lines and Histotypic Cultures by Clinically Relevant Low Doses of the Galactoside-Binding Mistletoe Lectin, A Component of Proprietary Extracts

Abstract

The toxic galactoside-specific lectin from mistletoe, a component of proprietary extracts with unproven efficacy in oncology, exhibits capacity to trigger enhanced secretion of proinflammatory cytokines at low doses (ng/ml or ng/kg body weight) and reductions of cell viability with increasing concentrations. To infer any tumor selectivity of this activity, cytofluorimetric and cell growth assays with a variety of established human tumor cell lines were performed. Only quantitative changes were apparent, and the toxicity against tumor cells was within the range of that of the tested fibroblast preparations from 5 donors. No indication for any tumor selectivity was observed. In kinetic studies with 8 sarcoma and 4 melanoma lines, this evidence for quantitative variability of the response in interindividual comparison was further underscored. At 50 pg lectin/ml x 10(5) cells, even a growth-stimulatory impact was noted in 5 of 12 tested cases. To mimic in vivo conditions with presence of cytokine-secreting inflammatory and stromal cells, exposure to the lectin was extended to histotypic cultures established from 30 cases of surgically removed tumor. As salient result, 5 specimens from 4 of the 8 tested tumor classes responded with a significant increase of [3H]-thymidine incorporation relative to controls during the culture period of 72 hours, when the lectin was present at a concentration in the described immunomodulatory range (1 ng/ml). A relation of this activity to the extent of the actual proliferative status of the reactive samples could not be delineated. Therefore, a non-negligible percentage of the established tumor cell lines (e.g., 3 from 8 sarcoma lines) can be markedly stimulated by the lectin at a very low dose and with dependence on the cell type. Furthermore, the feasibility to elicit a significant growth enhancement is likewise documented for human tumor explants in 16.6% of the examined cases. In view of the uncontrolled application of lectin-containing extracts in alternative/complementary medicine, the presented results on unquestionably adverse lectin-dependent effects in two culture systems call for rigorous examination of the clinical safety of this unconventional, scientifically entirely experimental treatment modality.

Complementary Therapies in Breast Cancer Patients

“…Based on the present status of clinical trials, a prolongation of life expectancy of breast cancer patients seems possible, but has not been definitely proven [53]. Although one research group [54] showed the growth stimulation of tumor cells by mistletoe, the results of the study could not be reproduced by other groups [55]. This study is, nevertheless, often cited by adversaries of mistletoe therapy in order to warn patients against this form of therapy.…”

The conformation of the C-glycosyl analogue of N-acetyl-lactosamine in the free state and bound to a toxic plant agglutinin and human adhesion/growth-regulatory galectin-1

“…Thus, as a first step, respective NMR experiments were performed to monitor binding of 1 to the mistletoe lectin. 22 Figure 4 shows the relevant section of the 1 H NMR spectrum of 1 upon addition of VAA, with a 1/ VAA molar ratio of ca. 20:1.…”

Lectin‐Based Drug Design: Combined Strategy to Identify Lead Compounds using STD NMR Spectroscopy, Solid‐Phase Assays and Cell Binding for a Plant Toxin Model

“…[7][8][9][10] Broad specificity and recognition of low-energy conformers ensures unselective toxicity. [1,9,[11][12][13][14][15][16][17] VAA tetramer toxicity can be neutralized using suitable inhibitors that compete with the cell-surface glycans as docking sites, [8,10,18,19] consequently impeding the attachment and internalization of the toxin to their target cells. Because of its detailed structural characterization including the architecture of the major binding site at physiologic pH, VAA is a suitable model for drug design studies.…”