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医学博士 甲第966号 平成17年2月18日 （埼玉医科大学）
Gene Expression of Thymidylate Synthase and Dihydropyrimidine Dehydrogenase in Gastric Cancer in Tems of Histolgical Type
Kenichi Suto (Department of Digestive and General Surgery, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan)
S-1 is a new oral fluorinated pyrimidine, in which tegafur (FT) has been combined with two substances as modulator; gimeracil (CDHP), and oteracil potassium (Oxo), in a molar ratio of 1:0.4:1 (FT:CDHP:Oxo). 5-FU is catabolized to dihydrofluorouracil by the first and rate-limiting enzyme, dihydropyrimidine dehydorogenase (DPD).The main mode of action of 5-FU is thought to be through its active metabolite suppresses thymidylate synthase (TS), that subsequently inhibit DNA syntheses. The predictive values of TS and DPD gene expressions in primary gastric cancer in terms of differentiated and undifferentiated type cases were also evaluated and the 2 gene expressions were retrospectively evaluated in patients with gastric cancer treated by a regimen containing S-1. The study population consisted of 78 patients with advanced gastric cancer who underwent surgical treatment and without S-1 chemotherapy 27 patients treated by S-1-alone for metastatic gastric cancer. Laser-captured micro dissection of malignant tissue was performed in formalin-fixed, paraffin-embedded specimens. After extraction RNA, TS and DPD gene expressions were measured by the real-time reverse transcriptional PCR method. TS gene expression was higher in differentiated type cases than undifferentiated type cases (p<0.001).However, DPD gene expression of undifferentiated type cases was statistically higher than that of differentiated type cases (p<0.05). There was no statistical difference in DPD gene expression in term of response in 27 cases treated with S-1. TS mRNA of responding tumors was statistically lower than that of nonresponding ones when treated with S-1 (p<0.005), and patients with low TS gene expression survived longer than those with high TS gene expression, with statistical significance (p<0.0001). TS and DPD gene expressions in primary gastric cancer differ according to degree of histological differentiation. In addition S-1 treatment effect for metastatic gastric cancer might be determined by depending on the amount of TS expressions, regardless of DPD gene expressions.