CHRISTOPHER BACHRAN:  SATURDAY 01 APRIL 2006, 10:10

A combination of saponin and chimeric adaptertoxins enhances the tumor therapeutic potential

Christopher Bachran¹, Iring Heisler¹, Matthias F. Melzig², Mark Sutherland^1,3, Hendrik Fuchs^1
1Institut für Klinische Chemie und Pathobiochemie, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany; ²Institut für Pharmazie – Pharmazeutische Biologie, Freie Universität Berlin, Königin-Luise-Str. 2+4. D-14195 Berlin, Germany; ³Present address: Institute of Cancer Therapeutics, University of Bradford, BD7 3AY Bradford, United Kingdom

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 385000-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.

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