Advantages and Limitations of LCLs for Evaluating the Pharmacogenomics ofAnticancer Agents

The greatest advantages of the use of CEPH cell lines for studying human variation in response to drugs is that they provide a system to perform phenotypic studies of anticancer agents that would be considered unsafe and unethical in healthy volunteers. The confounders of in vivo studies (metabolism, pharmacokinetics, clearance) are ignored, which can be considered both an advantage and disadvantage. CEPH cells can be grown under identical conditions; thus the phenotype to be tested is in a well-controlled, isolated system without the confounders present in vivo.

In contrast, it is questionable how well the results apply to a drug that will be administered to a patient and thus will undergo metabolism. If one is identifying pharmacodynamic markers of drug sensitivity, the model still holds much promise. A major advantage of the use of CEPH cell lines is the extensive genotypic data that is publicly available (www.cephb.fr/cephdb/), allowing the use of classical mapping techniques such as linkage analysis to define regions of the genome that co-segregate with the phe-notype without requiring extensive genotyping. In particular, the International HapMap Project used cell lines from these same families with more than 6 million SNPs typed in 3-6 members of CEPH families for association studies that can be used to determine if SNPs or haplotypes containing multiple SNPs explain the variation in drug sensitivity (www.hapmap.org/abouthapmap.html).

One limitation of LCLs or other human-derived cell lines is that they represent only one specific tissue type, which may or may not be appropriate when assessing a toxic effect that occurs in a different tissue (e.g., peripheral neuropathy, diarrhea). Another limitation is that EBV transformation can introduce phenotypic changes or expression changes that may affect the phenotype of interest. One must consider different ethnic populations when evaluating phenotype-genotype relationships, and the large pedigrees currently available are Caucasian. Despite these limitations, the cell model provides an opportunity for initial identification of important genes and variants that can be validated in further studies.

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