Effects of cisplatin and ORG.2766 in chick embryonic brain cell cultures.
The neurotoxicity of cisplatin and ORG.2766, both separately and in combination, was investigated using serum-free chick embryonic brain cell cultures. At low cisplatin concentrations glial cells were affected more than nerve cells. The onset of cisplatin toxicity was delayed, the major effects only being seen after the treatment was finished and when no free cisplatin was present in the culture medium. The data further indicate that the area under the graph of free cisplatin concentration in the culture medium against time (AUC) is a measure of cisplatin toxicity. The AUC of free cisplatin in the culture medium which causes a 50% reduction in the expression of glial fibrillary associated protein (GFAP) was similar to blood AUC values in humans known to induce neurotoxic effects in around 80% of patients. ORG.2766 at very high concentrations increased lysosomal activity, as measured by neutral red uptake, and the expression of GFAP. ORG.2766 did not influence the toxicity of cisplatin in culture.
Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach.
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Bruinink
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Birchler
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000633:toxicity; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006207:Half-Life; D008247:Lysosomes / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*
D000970:Antineoplastic Agents; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; C013765:Org 2766; D000324:Adrenocorticotropic Hormone; D002945:Cisplatin