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.