Gene expression profile of 5-fluorouracil metabolic enzymes in primary colorectal cancer: potential as predictive parameters for response to fluorouracil-based chemotherapy.
BACKGROUND
Thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyltransferase (OPRT) have been reported to be predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy. Therapy guided by chemotherapy sensitivity and resistance assays may lead to rational treatment decisions.


METHODS
mRNA expression of TS, DPD, TP, and OPRT were quantified by reverse-transcriptase polymerase chain reaction (RT-PCR) after harvesting from paraffin embedded specimens through microdissection. In vitro chemosensitivity testing by histoculture drug response assay (HDRA) was performed with fresh specimens of the primary tumor from 49 patients with colorectal cancer. Correlations between the results of a chemosensitivity test (the T/C ratio; the percentage of optical density of a tumor treated with anticancer drugs in relation to the optical density of the tumor cultured in RPMI 1640 medium only) and the gene expression were assessed.


RESULTS
The gene expression of TS, TP, and OPRT had no correlation with clinicopathological factors, survival, and T/C ratio. The DPD mRNA levels (0.295 vs. 0.381, p = 0.2460) and OPRT/DPD ratio (5.535 vs. 4.394. p = 0.226) had a weak correlation with the T/C ratio. Of the eleven patients who were actually treated with chemotherapy, the responders had higher OPRT/DPD ratios (8.065 vs. 4.081, p = 0.090).


CONCLUSIONS
The DPD mRNA level and OPRT/DPD ratio evaluated from paraffin embedded specimens are candidates for further evaluation as predictors of response against 5-fluorouracil-based chemotherapy in colorectal cancer.
Kinoshita
Mizunobu
M
Department of Surgery II, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
Kodera
Yasuhiro
Y
Hibi
Kenji
K
Nakayama
Goro
G
Inoue
Tamotsu
T
Ohashi
Norifumi
N
Ito
Yuichi
Y
Koike
Masahiko
M
Fujiwara
Michitaka
M
Nakao
Akimasa
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009962:Orotate Phosphoribosyltransferase / Q000096:biosynthesis / Q000235:genetics; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013939:Thymidine Phosphorylase / Q000096:biosynthesis / Q000235:genetics; D013940:Thymidylate Synthase / Q000096:biosynthesis / Q000235:genetics; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D013939:Thymidine Phosphorylase; D005472:Fluorouracil