Relevance To Drug Toxicities In Humans

While the use of immortalized cell lines has the obvious benefits of convenience for high-throughput analysis, ability to replicate, and avoiding exposure of toxic molecules to patients or volunteers, cell lines are not human patients. The cells only represent one of many cellular constituents of a human (B-lymphocytes), and one that is not a major concern for life-threatening toxicity. This cell lineage may not adequately represent GI tract, nerves, and the complete bone marrow milieu. The cell lines do not have a liver to evaluate pharmacokinetics nor an immune system or other dynamic processes that are important for the in vivo effects of many drugs. Indeed, most CYPs and transporters are down-regulated in CEPH cell lines and therefore will not be evaluable in the toxicity screens. However, the cell lines do offer a cell autonomous model of drug effect, in that any mechanism that is common to multiple cell lineage is likely to be represented in the CEPH cells.

The argument against any given cell lineage can be made for hepatocytes and/or human cancer cell lines, both of which are a major part of the drug development process. There is also an emphasis on the pharmacodynamic mechanisms of the drug effect, because of the absence of CYP/transport members. Because a drug's pharmacokinetics are usually adequately characterized as part of the preclinical and early clinical development, pharmacodynamics remains an area of needed research.Specific steps have been taken to try to understand how relevant the CEPH cell lines are to other cancer cell line systems.

The observed CEPH population mean IC50 for both docetaxel and 5-fluorouracil was similar to IC50 values observed across the NCI60 panel of human tumor cell lines (http://dtp.nci.nih.gov) (17). In addition, docetaxel- and 5-fluorouracil-induced cell death is mediated by caspase-3 cleavage, similar to that observed in tumor cells (17). These data are encouraging for the use of CEPH pedigrees as a discovery tool. However, the ultimate proof of the value of the cell-based models will be the human validation of markers derived from this process. These studies lie ahead and will help position cell-based models in their correct place in the drug development process.

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