Colorectal cancer with high-frequency microsatellite instability expresses high-level thymidine phosphorylase but not dihydropyrimidine dehydrogenase
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Recent clinical studies have reported that microsatellite instability (MSI) colorectal cancers show a high sensitivity to 5-FU, but these reports are contradictory to findings from in vitro analyses. In this study, we analyzed the relationship between MSI phenotypes and the expression of 5-FU metabolic enzymes in human colorectal cancer specimens. MSI phenotypes in 174 sporadic colorectal carcinomas were determined and grouped into the following three categories based on the Bethesda guidelines: high-frequency MSI (MSI-H), low-frequency MSI (MSI-L), and stable microsatellite (MSS). The expressions of dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) in tumor specimens were measured by enzymelinked immunosorbent assays. The ratio of TP to DPD expression (TP/DPD ratio) was calculated for each tumor. These three factors were compared with regard to MSI phenotypes by non-parametric and logistic regression analyses using cut-off values at their medians. MSI-L tumors were excluded from statistical analyses. Thirteen tumors were classified as MSI-H, 8 tumors as MSI-L, and 153 tumors as MSS. DPD expression did not differ between MSI-H tumors and MSS tumors. TP expression and the TP/DPD ratio were significantly higher in MSI-H tumors than in MSS tumors [TP, 160.1± 104.0 vs 97.3 ± 53.7 (Units/mg protein) (P=0.009); TP/DPD ratio, 3.04 ± 1.62 vs 2.07 ± 1.08, (P=0.016)]. These differences were also significant in multivariate analysis. In conclusion, these data suggest that 5-FU catabolic activity in cancer tissue does not differ between MSI-H and MSS tumors. However, 5-FU anabolic activity in cancer tissue is higher in MSI-H than in MSS colorectal carcinomas.
- 2013-04-00
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- Colorectal cancer with high-frequency microsatellite instability expresses high-level thymidine phosphorylase but not dihydropyrimidine dehydrogenase