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Real-time Cell Analysis with Roche´s xCELLigence System for the Early Detection of Hepatic Cytotoxicity

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The 3Rs concept of reducing, refining and replacing animal experimentation was developed by W.M.S. Russell and R.L. Burch in their book “The Principles of Humane Experimental Technique” more than 50 years ago. Today, early identification of toxic compounds using cell-based in vitro assays like Roche´s xCELLigence System can reduce the number of laboratory animals used for in vivo testing of suboptimal compounds that ultimately fail at later stages of drug testing.

A recent study from Roche Pharma and Roche Applied Science (1) describes a comprehensive workflow of in vitro techniques, including real-time cell analysis, biochemical assays, and gene expression analyzes for hepatotoxicity assessment.  

Hepatotoxic effects of the tested compounds were easily monitored using the xCELLigence System, to generate Cell Index (CI) profiles that quantitate the onset and progress of compound-induced cell death. Compared to routinely used biochemical endpoint assays, the xCELLigence System showed a higher sensitivity 24 hours post-treatment.

Resulting kinetic profiles monitored toxicity from the beginning to end of the experiment; profiles like this are not possible using endpoint assays. Continuous CI recording quantifies cytotoxicity identifying the optimal time point for IC50 calculations. Interestingly, CI profiles revealed dose-dependent hepatocyte responses to the tested compounds as early as 6 hours post-treatment.

In the following, the researchers investigated hepatotoxic effects by gene expression analysis at these early time points. Whole genome microarray analysis revealed a significant reproducible change in gene expression 6 hours post-treatment, coinciding with the onset of cell death found in the xCELLigence System data. Subsequent quantitative RT-PCR for a subset of selected genes revealed a significant change in gene expression 6 hours after compound administration, indicating early onset of gene regulation within the first hours post-treatment.

The results of this study emphasize the added value of the described workflow of real-time cell analysis, biochemical endpoint assays, and gene expression analyzes. Continuous monitoring using the xCELLigence System easily identified modest cellular effects, providing a versatile way for pinpointing times for downstream proteomic and genomic analyses. Using Roche NimbleGen microarrays for appropriately-timed molecular analysis assures meaningful and reproducible whole genome expression data for identifying new target genes and possible biomarkers.

Gene expression analyzes using Universal ProbeLibrary Assays are also now available as pre-tested Real-Time ready Assays. Combining the xCELLigence System with both well-established Roche endpoint assays and this new generation of Roche gene expression assays are designed by Roche to improve the predictive quality of early safety evaluations that may go on to reduce current levels of animal testing in the future.