Expression level of thymidylate synthase mRNA reflects 5-fluorouracil sensitivity with low dose and long duration in primary colorectal cancer.
OBJECTIVE
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.
Okumura
Kenji
K
Department of Surgery, Shiga University of Medical Science, Seta-tsukinowacho, Otsu, Shiga, 520-2192, Japan. kenjiok@belle.shiga-med.ac.jp
Mekata
Eiji
E
Shiomi
Hisanori
H
Naitoh
Hiroyuki
H
Abe
Hajime
H
Endo
Yoshihiro
Y
Kurumi
Yoshimasa
Y
Tani
Tohru
T
D000368:Aged; D000963:Antimetabolites / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism; D013940:Thymidylate Synthase / Q000096:biosynthesis* / Q000235:genetics
D000963:Antimetabolites; D005819:Genetic Markers; D012333:RNA, Messenger; D003094:Collagen; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil