Relationship between the expression of 5-FU-metabolizing enzymes in cancer tissue and the effect of fluoropyrimidine-based chemotherapy.

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In the present study, we immunohistochemically evaluated the relationship between the expression of 5-FU-metabolizing enzymes and the effect of fluoropyrimidine-based chemotherapy in gastrointestinal cancers. The results were summarized as follows :1) The avoidance of high temperature during section stretching on a hot plate was one of the important factors to suitably immunostain orotate phosphoriboayltransferase (OPRT) in formalin-fixed, paraffin-embedded sections. The specificity of OPRT immunostaining was confirmed by the preabsorption experiment. The OPRT immunostaining scores were correlated with the enzyme activities or the ELISA levels.2) Expression pattern of fluoropyrimidine-metabolizing enzymes, including OPRT, dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and thymidylate synthase (TS), differed from cancer to cancer. Their expression patterns in cancer tissue were generally similar to those of the normal counterparts.3) The intensity of OPRT immunostaining was generally stronger in gastric cancer tissues than in normal gastric mucosa, and in intestinal type cancers than in diffuse type cancers.4) In advanced gastric cancer, the TS-and/or p53-high phenotype was a predictor of the resistance to neoadjuvant chemotherapy with S-1 plus cisplatin. There was no relationship between the expression of OPRT and DPD, and the chemotherapeutic effects.5) Most of α-fetoprotein-producing adenocarcinoma of the digestive organs (APAD) showed the TP-low and metallothionein-low phenotype, suggesting that APAD should be sensitive to cisplatin, but resistant to N^4-pentyloxycarbonyl deoxyfluorocytidine (capecitabine) and 5'-deoxyfluorouridine (5'-DFUR).6) Neither OPRT nor DPD expression was correlated to the effects of neoadjuvant chemotherapy with uracil plus ftorafur or 5'-DFUR in advanced colorectal cancers.