Combined application of saponin and chimeric toxins drastically enhances the targeted cytotoxicity on tumor cells

Immunotoxins have to be administered in high doses due to low cytosolic uptake with the consequence of severe side effects. Recently we found that the cytotoxic activity from Agrostemma githago seeds can be attributed to a synergistic toxicity of a triterpenoid saponin and a ribosome-inactivating pr...

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Bibliographic Details
Published in:Journal of controlled release 2005-08, Vol.106 (1), p.123-137
Main Authors: Heisler, Iring, Sutherland, Mark, Bachran, Christopher, Hebestreit, Philipp, Schnitger, Anna, Melzig, Matthias F., Fuchs, Hendrik
Format: Article
Language:English
Subjects:
Agrostemma githago
Animals
Biological and medical sciences
Cancer therapy
Caryophyllaceae - chemistry
Cell Line, Tumor
Cell Survival - drug effects
Drug Combinations
Drug Synergism
Epidermal growth factor
General pharmacology
Humans
Immunotoxin
Immunotoxins - pharmacology
Medical sciences
Mice
NIH 3T3 Cells
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Plant Proteins - pharmacology
Recombinant chimeric toxin
Saponin
Saponins - pharmacology
Saporin
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Summary:Immunotoxins have to be administered in high doses due to low cytosolic uptake with the consequence of severe side effects. Recently we found that the cytotoxic activity from Agrostemma githago seeds can be attributed to a synergistic toxicity of a triterpenoid saponin and a ribosome-inactivating protein. Here we investigated whether saponins are able to enhance the efficacy of a receptor-specific chimeric toxin consisting of saporin-3, epidermal growth factor and a molecular adapter previously shown to reduce side effects on non-target cells. Pre-applied saponin enhances the target cell-specific cytotoxic effect, dependent on the cell line, between 3560- and 385,000-fold with an IC 50 up to 0.67 pM. Non-target cells are not affected at the same concentration. At the optimal concentrations of the chimeric toxin and saponin application of either one of the components shows no cytotoxicity at all proving a synergistic effect. In the presence of saponin ligand-free saporin-3 does not exhibit any cytotoxic effect up to 0.1 nM providing further evidence for an increased specificity. This synergistic effect is in the same order of magnitude as in a mouse model. Our investigations clearly demonstrate that a combined administration of saponin and chimeric toxins opens up a promising perspective for tumor therapy.
ISSN:0168-3659
1873-4995
DOI:10.1016/j.jconrel.2005.04.006