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医学博士 乙第959号 平成16年12月24日 （埼玉医科大学）
Gene Expression of Thymidylate Synthase and Dihydropyrimidine Dehydrogenase in Primary Colorectal Cancer
Naoto Nishi (Department of Digestive and General Surgery, Saitama Medical School, Moroyama, Iruma-gun, Saitama 350-0495, Japan)
BACKGROUND: Thymidylate synthase (TS) is a target enzyme for 5-fluorouracil (5-FU), and dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme for degradation of 5-FU. Recently, determination of intratumoral TS and DPD is of clinical interest because elevated TS and DPD levels can influence the tumor response to 5-FU based chemotherapy through increased inactivation of the agent in tumor cells. In the present study, TS and DPD mRNA levels were evaluated in 12 cases of primary colorectal cancer with liver metastasis that were surgically resected. Moreover, TS and DPD mRNA levels of primary colorectal cancer with metastatic tumor were analysed in terms of the response of UFT/LV based chemotherapy. PATIENTS and METHODS: (1) TS and DPD mRNA levels were evaluated in 12 surgical cases of primary colorectal cancer with liver metastasis. No one had received 5-FU based chemotherapy prior to the study. (2) TS and DPD mRNA levels of the metastatic colorectal cancer patient who received the UFT/LV based chemotherapy were investigated in 37 cases. RESULT: (1) Measurement of the TS and DPD mRNA level in both primary and metastatic lesions were possible in all 12 cases. The TS mRNA level in hepatic metastatic foci was significantly lower than that in primary lesions (median TS/GAPDH ratio 0.89 and 1.09 respectively, p=0.0047, Wilcoxon signed-ranks test). The DPD mRNA level in hepatic metastatic foci was significantly higher than that in primary lesions (median DPD/GAPDH ratio 0.87 and 0.48 respectively, p=0.0047). Both TS and DPD mRNA had linear relationship between primary colorectal cancer and metastatic liver tumor. (2) The response rate of UFT/LV based chemotherapy with low-TS mRNA (TS≦1.0) was significantly higher than that with high-TS mRNA (TS>1.0) (P=0.038). Similarly, the response rate with low-DPD mRNA (DPD≦0.5) was statistically higher than that with high-DPD mRNA (DPD>0.5) (P<0.0001). The patients with low expression of TS mRNA had significantly longer survival than patients with high value of TS mRNA (P=0.0069). The patients with low expression of DPD mRNA had also significantly longer survival than patients with a high value of DPD mRNA (P<0.0001). CONCLUSION: The results of this study showed that TS and DPD gene expression in primary colorectal cancer is associated with metastatic tumor. It will become possible to predict the efficacy of the UFT/LV based chemotherapy for liver metastasis by analyzing TS and DPD levels of colorectal cancer.