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Expression level of thymidylate synthase mRNA reflects 5-fluorouracil sensitivity with low dose and long duration in primary colorectal cancer.

Okumura K, Mekata E, Shiomi H, Naitoh H, Abe H, Endo Y, Kurumi Y, Tani T

Department of Surgery, Shiga University of Medical Science, Seta-tsukinowacho, Otsu, Shiga, 520-2192, Japan. kenjiok@belle.shiga-med.ac.jp

OBJECTIVES: To investigate the prognostic marker for the adjuvant chemotherapy of primary colorectal carcinoma. METHODS: Primary colorectal cancer tissue from 24 patients was investigated to evaluate the relationship between the mRNA expression level of several 5-fluorouracil (5-FU)-related metabolic enzymes (thymidylate synthase, TS; dihydropyrimidine dehydrogenase, DPD; and thymidine phosphorylase, TP) and chemosensitivity to two different 5-FU doses and duration (1: 5-FU concentration 1.0 microg/mL (7.68 microM), 24 h exposure and 2: 5-FU concentration 0.3 microg/mL (2.30 microM), 144 h exposure). Chemosensitivity and mRNA expression levels were measured using collagen gel droplet embedded culture drug sensitivity tests and real-time quantitative reverse transcription-polymerase chain reaction. Clinicopathological features and chemosensitivity were also compared. RESULTS: The TS mRNA expression level was significantly higher in the 5-FU resistant group (T/C > 60%) compared with the 5-FU sensitive group (T/C < 60%) in both 5-FU regimens (1: 5.03 +/- 0.92 vs. 1.58 +/- 0.76, p < 0.01, 2: 4.88 +/- 0.91 vs. 0.96 +/- 0.20, p < 0.001). The group with the higher TS mRNA expression level (>3.83, the average) were more resistant to both 5-FU regimens than those with lower TS mRNA (<3.83) (1: T/C = 80 vs. 66%, p = 0.11, 2: T/C = 89 vs. 64%, p < 0.005). The TS mRNA expression level inversely correlated with the sensitivity to the latter 5-FU regimen (R = 0.577, p < 0.01). There were no relationships between chemosensitivity to 5-FU and the mRNA expression level of DPD and TP and clinicopathological factors. CONCLUSIONS: The TS mRNA expression level might be a good marker of chemosensitivity to 5-FU in primary colorectal cancer, especially the sensitivity to low dose 5-FU with a long duration.

Published 9 January 2008 in Cancer Chemother Pharmacol, 61(4): 587-94.
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