[Innovative cell culture methods in drug development] [Article in German] LINZ 2000

Abstract

Animal studies necessary for drug registration are time-consuming, costly, and often stressful for the animals. Toxicological screening of drug candidates early in development with in vitro cell culture systems is therefore of relevance. In contrast to animal studies, in vitro cell culture methods are characterised by a low compound requirement and a short duration. Additionally it is possible to include mechanistic studies or to test for toxicity specific to humans. Therefore, early toxicological screening can provide a useful support for selecting the most promising drug candidate. Primary hepatocytes can be used to measure the cytotoxicity of a test compound. These results can be used to estimate general toxicity. Measuring endpoints like apoptosis, redox status, or gene expression profiles can help to answer mechanistic questions. The use of primary human hepatocytes provides early predictivity for hepatotoxicity specific to humans. Since teratogenic findings in animal studies often lead to abandonment of development, it is reasonable to use an in vitro embryotoxicity assay for early determination of the teratogenic potential of a compound, e.g. the embryonic stem cell test (EST) which was recently developed by ZEBET. In the EST embryonic stem cells are investigated for their preserved capability to differentiate into cardiomyocytes following drug exposure. In comparison cytotoxicity of the test substance is analysed in embryonic stem cells and in differentiated fibroblast cells. In a validation study initiated by ECVAM the EST shows a high correlation with in vivo data.