Cytotoxicity Panel

Understand potential liabilities of new molecular entities with a panel of gold standard in vitro assays

Drug Discovery is a resource intensive effort and high rates of attrition in late stage discovery is an unacceptable outcome.  During the development process it is important to identify any potential liabilities associated with new molecular entities (NMEs). Typically in the Lead-Optimization phase it is important to know if a new compound will produce animal or human toxicity at concentrations relevant to those expected to be therapeutic. The IONTOX cytotoxicity panel helps companies understand potential liabilities of NMEs through the prediction of in vivo responses to a compound with in vitro data.

Cytotoxicity Panel Service Details

The cytotoxicity panel assessment works by creating a multiple endpoint concentration-response profile of biochemical effects in relevant cell models, which provide the mechanism-based data required to predict animal or human adverse events.  When these response profiles are compared to estimated, or actual Cmax values it is possible to predict subcellular targets and likely in vivo responses.

Cytotoxicity Panel Overview & Background

Before running a predictive cytotoxicity panel organizations often screen compounds with a single assay for cell viability. A single assay for cell health can provide important information concerning the relative toxicity of one compound versus another in the same group. Single assays such as IONTOX's ATP cell viability assay (FastTox™) tell scientists how chemical changes in the development molecule impacts general cell health.  A cytotoxicity panel provides the next tier of information with insights into the subcellular mechanisms that are causing an adverse effect.

In the cytotoxicity panel offered by IONTOX (example data in the figure to the left), Membrane integrity (GST), cell number (propidium iodide), and mitochondrial function (MTT and ATP) are all monitored over a broad range of exposure concentrations. When running these assays, care is taken to ensure that the concentration where efficacy is half maximal (EC50) is included.  When the chemical rotenone was tested, the data in the panel of four graphs above tells an interesting story.  After a 24 hr exposure, there was no cell death as determined by glutathione S-transferase leakage (GST).  There was a reduction in cell number (upper right panel) and a pronounced reduction in both ATP and MTT (lower left panel).   Taken together (lower right panel) these data demonstrate that the test molecule (rotenone) has its primary effect on mitochondria, causing a inhibition of complex II (MTT), and a reduction in cellular ATP levels.  The loss of cellular energy resulted in a slowing of cell replication.  Clearly, vastly different conclusions would have been made if only ATP or only membrane integrity had been monitored.

By comparing the toxic concentration producing a half maximal effect (TC50) to the EC50 it is possible to develop an in vitro therapeutic index.  The plasma concentration where toxicity would be expected to occur can also be estimated from these data.

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