Prediction of sensitivity to 5-fluorouracil by quantitative measurement of 5-fluorouracil metabolism-relating gene expression in gastric and colorectal cancer

Abstract

4143 Background: Five-fluorouracil (5-FU) is still one of the key-drug for chemotherapy in gastric and colorectal cancer. Therefore, prediction of 5-FU sensitivity is of great importance for chemotherapy in these types of cancer. In the present study, we investigated the role of gene expression levels of 5-FU metabolism-relating enzymes on tumor sensitivity to 5-FU in gastric and colorectal cancer. The investigated genes were as follows; tymidylate synthase (TS), orotate phosphoribosyl transferase (OPRT), thymidine phosphorylase (TP), ribonuclease reductase (RNR) and dihidropyrimidine dehydrogensa (DPD). Methods: Tumors were obtained from 45 patients with gastric cancer and 30 patients with colorectal cancer. Gene expression levels were determined by quantitative real-time reverse transcription polymerase chain reaction. TS and DPD protein levels were also determined by ELISA. Tumor sensitivity to 5-FU was evaluated by in vitro ATP assay. Results: Although DPD mRNA level did not correlate with DPD protein level, TS mRNA level significantly correlated with TS protein level (r=0.535, p=0.0002). There were significant correlations between TP and DPD, OPRT and RNR gene expression levels and between OPRT and RNR gene expression levels. In concerning with the 5-FU sensitivity, DPD expression levels in gastric(r=-0.635, p=0.0246) and colorectal cancer (r=- 0.469, p=0.0419) and TP expression level in gastric cancer (r=-0.525, p=0.080) showed weak inverse correlation with 5-FU sensitivity. However, OPRT/DPD mRNA ratio significantly correlated with 5-FU sensitivity in both gastric (r=0.780, p=0.0104) and colorectal cancer (r=0.674, p=0.0097). High OPRT/DPD ratio resulted in high sensitivity to 5-FU. Conclusions: From these results, it is suggested that tumors with high anabolic enzyme mRNA and low catabolic enzyme mRNA show remarkable sensitivity to 5-FU in gasric and colorectal cancer. Quantitative measurement of 5-FU metabolism-relating gene expression levels may be a good indicator for predicting sensitivity to 5-FU in patients with gastric and colorectal cancer. No significant financial relationships to disclose.