The distribution of saponins in vivo affects their synergy with chimeric toxins against tumours expressing human epidermal growth factor receptors in mice

• Published in: British journal of pharmacology 2010-01, Vol.159 (2), p.345-352
• Main Authors: Bachran, C, Weng, A, Bachran, D, Riese, SB, Schellmann, N, Melzig, MF, Fuchs, H
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological and medical sciences; cancer therapy; Caryophyllaceae; Cell Line; Cell Line, Tumor; chimeric toxin; Drug Synergism; Epidermal growth factor; Epidermal Growth Factor - genetics; Female; Gypsophila paniculata; Humans; immunotoxin; Immunotoxins - genetics; Immunotoxins - pharmacokinetics; Immunotoxins - pharmacology; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Pharmacology. Drug treatments; Receptor, Epidermal Growth Factor - biosynthesis; Receptor, Epidermal Growth Factor - genetics; Research Papers; Ribosome Inactivating Proteins, Type 1 - genetics; Rodents; Saponins - genetics; Saponins - pharmacokinetics; Saponins - pharmacology; Saponinum album; saporin; Tissue Distribution; Toxins; Tritium; Tumors; Urine
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2009.00543.x

Background and purpose:  Certain saponins synergize with antitumour drugs to enhance their efficacy, but the mechanisms underlying this synergy in vivo are not well studied. Here, we describe the distribution of Saponinum album (Spn) from Gypsophila paniculata L. in mice after subcutaneous injection. Experimental approach:  The [3H]‐labelled Spn used for in vivo experiments was biologically active, as it still increased the cytotoxicity of a chimeric toxin in vitro. Distribution of [3H]‐Spn was measured in BALB/c mice, with or without subcutaneous tumours in the flank. Labelled Spn was subcutaneously injected in the neck, and samples of organs, blood, urine and tumour tissue were analysed for radioactivity, 5–240 min after the injection. Key results:  The majority of [3H]‐Spn distributed within 10 min throughout the entire animal, with high levels of radioactivity in the urine by 30 min. No preferential accumulation in tumour tissue or other organs was observed. In tumour‐bearing mice, using a sequential combination of Spn (given first) and a chimeric toxin against the epidermal growth factor receptor, ErbB1, we tested two different pretreatment times for Spn. There was high antitumour efficacy (66% inhibition of tumour growth) after 60 min pre treatment with Spn, but no significant inhibition after 10 min pre treatment with Spn. Conclusions and implications:  [3H]‐Spn was rapidly cleared from the mice after s.c. injection, and antitumour synergy with chimeric toxins was correlated with the removal of excess Spn from tissues. Disposition of Spn in vivo may critically determine antitumour synergy with chimeric toxins.