期刊
MOLECULAR ONCOLOGY
卷 7, 期 3, 页码 475-483出版社
WILEY
DOI: 10.1016/j.molonc.2012.12.004
关键词
Targeted toxin; Synergistic toxicity enhancement; Saponaria saponins; Ligand-mediated therapeutics; Saporin; Epidermal growth factor
类别
资金
- Alexander von Humboldt Foundation
- German Research Foundation (DFG) [FU 408/6-1, TH1810/1-1, WE 4784/1-1]
Targeted toxin-based therapeutics are hindered by poor intracellular uptake, limited stability and non-specific immune stimulation. To address these problems, ligand-targeted toxins in combination with low dose saponin mixtures have been adapted and tested in vivo in the past, however, undefined saponin raw mixtures are not suitable for use in clinical development. In the present work we therefore used a targeted toxin (Sap3-EGF, i.e. saporin fused to epidermal growth factor) in combination with a structurally defined isolated saponin m/z 1861 (SO-1861). In vitro evaluation confirmed a 6900-fold enhancement in the cytotoxic efficacy of Sap3-EGF against TSA-EGFR target cells. The required dose of the targeted toxin was appreciably reduced and there was a highly synergistic effect observed. An ex vivo hemolysis assay showed no or very less hemolysis up to 10 mu g/mL of SO-1861. In the acute toxicity studies SO-1861 was found to be non-toxic up to a dose of 100 mu g/treatment. The enzymes aspartate aminotransferase, alanine aminotransferase, and glutamate dehydrogenase did not show any statistically significant liver damage, which was further confirmed by histological examination. Additionally, creatinine was also similar to the control group thus ruling out damage to kidney. In vivo studies in a syngeneic BALB/c tumor model characterized by EGFR overexpression were done by applying 30 mu g SO-1861 and 0.1 mu g Sap3-EGF per treatment. A more than 90% reduction (p<0.05) in the average tumor volume was observed by this combined therapy. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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