Using Pharmacogenomic Tumor Profiling to Identify Biomarkers of 5-fluorouracil Response in Colorectal Cancer

The chemotherapeutic agent 5-fluorouracil (5-FU) remains the drug of choice for the treatment of metastatic colorectal cancer, despite the fact that poor patient response to the drug due to acquired or inherent drug resistance is a major clinical problem. To be able to predict an individual patient's response to 5-FU would facilitate the design of chemotherapeutic regimens tailored according to the individual patient and tumor profile. Pharmacogenomic studies provide information as to how variability on a genome-wide scale influences drug response, and are facilitated by high throughput technologies such as genomic and expression microarrays and single nucleotide polymorphism (SNP) assays. Not surprisingly, such investigations are taking the place of genetic studies that investigate associations between drug response and genetic alterations for one individual gene. This reflects the growing awareness that cancer drug response is multi-faceted. The cellular mechanisms underlying drug resistance can involve alterations at the single gene and/or genomic level on multiple biological regulatory pathways, e.g., cell cycle progression, apoptotic, and DNA repair pathways. This review will provide an update on how pharmacogenomic studies are being used to dissect the cellular mechanisms underlying drug response and drug resistance in colorectal cancer in order to identify novel biomarkers of 5-FU response, and how knowledge gained from transcriptional profiling studies of colorectal tumors is serving as a guide for optimization of current chemotherapeutic strategies and for design of new treatment strategies.