Dihydropyrimidine Dehydrogenase and Messenger RNA Levels in Gastric Cancer: Possible Predictor for Sensitivity to 5-Fluorouracil

Abstract

We investigated the correlation between tumor sensitivity to 5‐fluorouracil (5‐FU) and enzymatic activities of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in human gastric cancer specimens. Forty‐one patients with advanced gastric cancer gave informed consent and were enrolled in the study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD messenger RNA (mRNA) levels. TS and DPD enzyme activity and mRNA levels were also measured in resected tumor tissue samples obtained after surgical resection. TS and DPD activity were measured using the TS‐binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi‐quantitative reverse transcription‐polymerase chain reaction (RT‐PCR), with co‐amplification of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) as an internal standard. 5‐FU sensitivity of resected tumor specimens was measured by the tetrazolium‐based colorimetric assay (MTT assay). Both TS and DPD mRNA levels correlated well between biopsied and resected tumor specimens. A statistically significant correlation was also observed between mRNA levels in biopsied specimens and enzymatic activities in resected specimens. DPD levels significantly correlated with 5‐FU sensitivity, such that high DPD activity and high DPD mRNA levels resulted in low sensitivity to 5‐FU. In contrast, no correlation was observed between TS activity or TS mRNA levels and 5‐FU sensitivity. We conclude that tumor DPD mRNA level, as assessed from biopsy specimens obtained by gastrofiberscopy, may be a useful indicator in predicting tumor sensitivity to 5‐FU in patients with gastric cancer.