Drug Discovery


Figure 3


Requirements to support large-scale manufacturing of stem cells


liver-derived cell line such as HepG2. Despite rou- tine use for investigative toxicity, both of these options present significant drawbacks:


l Primary human hepatocytes are derived from fresh liver tissue, typically sourced from cadavers or cancer resections. Supply of these cells can be limit- ed and the tissue can vary widely among donors. l Primary hepatocytes cannot be sustained for more than a few days in culture without losing function. Securing a consistent supply of cells requires repetitive sourcing, which further con- tributes to variability. l Immortalised hepatocyte cell lines can be cul- tured indefinitely, which addresses the supply and variability issues associated with use of primary human hepatocytes. However, these cells display distinct differences from normal liver cells and may not exhibit normal cell behaviour or response. For example, most cytochrome P450


18


enzymes (responsible for drug metabolism) are expressed only weakly in HepG2 cells compared to normal human hepatocytes.


Although the pharmaceutical industry relies on animal models for preclinical metabolism and tox- icity testing, these models also have limitations. Animal models may not be fully and reliably pre- dictive of human toxicity. In addition, animal mod- els are low throughput, expensive and raise ethical concerns for some.


Cost and throughput often relegate use of ani- mal models to the later stages of preclinical devel- opment. By this time, a company has invested sig- nificant time and resources in a lead compound. This delayed evaluation of toxicity contributes to the high failure rate of compounds in late stage preclinical testing, which is extremely costly. Earlier, more effective assessment of drug can- didate toxicity has the potential to reduce the


Drug Discovery World Spring 2011


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