Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer: Possible predictor for sensitivity to 5-fluorouracil

We investigated the correlation between tumor sensitivity to 5-fluorouracil (5-FU) and enzymatic activities of thymidylate synthetase (TS) and dihydro pyrimidine dehydrogenase (DPD) in human gastric cancer specimens. Forty-one patients with advanced gastric cancer gave informed consent and were enrol led in the study. Biopsy specimens of gastric cancer were obtained preopera tively through gastrofiberscopy and used to determine TS and DPD messenger RNA (mRNA) levels, TS and DPD enzyme activity and mRNA levels were also mea sured in resected tumor tissue samples obtained after surgical resection. T S and DPD activity were measured using the TS-binding assay and a radioenzy matic assay, respectively, while mRNA levels were measured by semi-quantita tive reverse transcription-polymerase chain reaction (RT-PCR), with co-ampl ification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an interna l standard. 5-FU sensitivity of resected tumor specimens was measured by th e tetrazolium-based colorimetric assay (MTT assay), Both TS and DPD mRNA le vels correlated well between biopsied and resected tumor specimens. A stati stically significant correlation was also observed between mRNA levels in b iopsied specimens and enzymatic activities in resected specimens. DPD level s significantly correlated with 5-FU sensitivity, such that high DPD activi ty and high DPD mRNA levels resulted in low sensitivity to 5-FU, In contras t, 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 bio psy specimens obtained by gastrofiberscopy, may be a useful indicator in pr edicting tumor sensitivity to 5-FU in patients with gastric cancer.