[Prediction of sensitivity to 5-fluorouracil (5-fu) by metabolic and target enzyme activities in colon cancer].
BACKGROUND
5-Fluorouracil (5-FU) and its derivatives are widely known as some of the most commonly prescribed anticancer drugs, especially for gastrointestinal cancer. Orotate phosphoribosyl transferase (OPRT), dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are initial key enzymes in the 5-FU metabolic pathway. The activities of these enzymes may have the potential to affect the chemosensitivity of 5-FU.


OBJECTIVE
This study was designed to investigate the effect of OPRT, DPD and TS in sensitivity to 5-FU.


METHODS
We measured OPRT, DPD and TS activities in 11 colonic cancer tissues. The Collagen Gel Droplet Embedded Culture Drug Sensitivity Test (CD-DST) was used in an in vitro chemosensitivity assay. In these samples, the correlation between sensitivity to 5-FU and enzyme activities was investigated.


RESULTS
There were no correlations among OPRT, TS activities and sensitivity to 5-FU. In contrast, there was a significant inverse correlation (r=-0.738) between DPD activity and 5-FU sensitivity. With regression analysis, the coefficient of determination of the activity of the three enzymes versus the sensitivity to 5-FU was 0.61.


CONCLUSIONS
Though measuring OPRT, DPD, TS activities is valuable for prediction of sensitivity to 5-FU, DPD is considered to be the most important predictive factor of 5-FU sensitivity. To improve its accuracy, the finding of a fourth factor such as P-glycoprotein and multidrug resistance-associated proteins (MRP), to be added to OPRT, DPD and TS, is desired.
Yamada
Takeshi
T
Dept. of Surgery, Nippon Medical School Chiba Hokusou Hospital.
Tanaka
Noritake
N
Yokoi
Kimiyoshi
K
Ishikawa
Noriyuki
N
Seya
Tomoko
T
Horiba
Kouji
K
Kanazawa
Yoshikazu
Y
Shirakawa
Takashi
T
Ohkawa
Keiichi
K
Kudoh
Hidenori
H
Koizumi
Michihiro
M
Yoshioka
Masato
M
Shinji
Seiichi
S
Yamashita
Kiyohiko
K
Tajiri
Takashi
T
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008875:Middle Aged; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D005472:Fluorouracil