Gene expression of 5-fluorouracil metabolic enzymes in primary colorectal cancer and corresponding liver metastasis

Purpose: Expression of thymidylate synthase (TS) and the 5-fluorouracil (5-FU) metabolic enzymes, including dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), and uridine phosphorylase (UP), has been reported to be associated with the sensitivity to 5-FU-based chemotherapy in colorectal cancer. We evaluated the correlation of the expression of these genes between primary tumors and corresponding liver metastases. Method: The mRNA levels of TS, DPD, OPRT, TP, and UP were measured by real-time quantitative RT-PCR in samples from 23 consecutive patients with both primary colorectal adenocarcinoma and liver metastasis. Results: The DPD, OPRT, TP, and UP mRNA levels were significantly higher in liver metastases than in primary tumor (expression in relation to that of beta-actin mRNA: 0.42 vs 0.16, P = 0.00053; 1.4 vs 0.92, P 0.016; 23 vs 11, P=0.00014; 0.36 vs 0.25, P=0.0026; respectively). However, the TS mRNA level did not differ significantly between liver metastases than primary tumor (0.20 vs 0.16, P=0.28). No correlation was observed for any gene between primary tumor and liver metastases. In both primary tumor and liver metastasis, the TS mRNA levels correlated significantly with the OPRT mRNA level (primary r(s)=0.83, P=0.00000081; liver metastasis r(s)=0.49, P=0.017), while the DPD mRNA level correlated significantly with the TP mRNA level r(s)=0.81, P=0.0000024; r(s)=0.63, P=0.0014; respectively). Conclusions: The differential gene expression of 5-FU metabolic enzymes between primary colorectal cancer and corresponding liver metastases should be taken into consideration when estimating the sensitivity to 5-FU-based chemotherapy in colorectal cancer. The gene expression of TS and OPRT, which are involved in de novo pyrimidine synthesis, and that of DPD and TP, may be coregulated.