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 MSIphenotypes and the expression of 5-FU metabolic enzymes in human colorectal cancer specimens. MSI phenotypes in 174sporadic colorectal carcinomas were determined and grouped into the following three categories based on the Bethesdaguidelines: high-frequency MSI (MSI-H), low-frequency MSI (MSI-L), and stable microsatellite (MSS). The expressions ofdihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP) in tumor specimens were measured by enzymelinkedimmunosorbent assays. The ratio of TP to DPD expression (TP/DPD ratio) was calculated for each tumor. These threefactors were compared with regard to MSI phenotypes by non-parametric and logistic regression analyses using cut-off valuesat their medians. MSI-L tumors were excluded from statistical analyses. Thirteen tumors were classified as MSI-H, 8 tumorsas MSI-L, and 153 tumors as MSS. DPD expression did not differ between MSI-H tumors and MSS tumors. TP expression andthe 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/mgprotein) (P=0.009); TP/DPD ratio, 3.04 ± 1.62 vs 2.07 ± 1.08, (P=0.016)]. These differences were also significant in multivariateanalysis. In conclusion, these data suggest that 5-FU catabolic activity in cancer tissue does not differ between MSI-Hand MSS tumors. However, 5-FU anabolic activity in cancer tissue is higher in MSI-H than in MSS colorectal carcinomas.
- 長崎大学医学部の論文
長崎大学医学部 | 論文
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