Dihydropyrimidine Dehydrogenase Levels in Colorectal Cancer Cells Treated with a Combination of Heat Shock Protein 90 Inhibitor and Oxaliplatin or Capecitabine

Purpose: Dihydropyrimidine dehydrogenase (DPD) is the principal enzyme in the catabolism of fluoropyrimidine drugs including capecitabine. A recent report has suggested that oxaliplatin chemotherapy is associated with elevated DPD levels and chemoresistance pattern. As a newly developed chemotherapeutic agent, 17allyloamino17demethoxygeldanamycin (17AAG) can be effective in combination therapy with oxaliplatin and capecitabine in colorectal cancer (CRC). DPD expression level can be a predictive factor in oxaliplatin and capecitabinebased chemotherapy. We evaluated DPD in mRNA and protein levels with new treatments: 17AAG in combination with oxaliplatin and capecitabine in HT29 and HCT116 cell lines. Methods: Drug sensitivity was determined by the watersoluble tetrazolium1 assay in a previous survey. Then, we evaluated the expression levels of DPD and its relationship with the chemotherapy response in capecitabine, oxaliplatin, and 17AAG treated cases in single and combination cases in two panels of CRC cell lines. DPD gene and protein expression levels were determined by realtime polymerase chain reaction and western blotting assay, respectively. Results: DPD gene expression levels insignificantly increased in singletreated cases versus untreated controls in both cell lines versus controls. Then, the capecitabine and oxaliplatin were added in double combinations, where DPD gene and protein expression increased in combination cases compared to prechemotherapy and single drug treatments. Conclusion: The elevated levels of cytotoxicity in more effective combinations could be related to a different mechanism apart from DPD mediating effects or high DPD level in the remaining resistance cells (druginsensitive cells), which should be investigated in subsequent studies.