title: [Prediction of sensitivity to 5-fluorouracil (5-fu) by metabolic and target enzyme activities in colon cancer].
abstract: 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.
authors.affiliation: Dept. of Surgery, Nippon Medical School Chiba Hokusou Hospital.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamada
authors.forename: Noritake
authors.initials: N
authors.lastname: Tanaka
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Yokoi
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Tomoko
authors.initials: T
authors.lastname: Seya
authors.forename: Kouji
authors.initials: K
authors.lastname: Horiba
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kanazawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Shirakawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohkawa
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kudoh
authors.forename: Michihiro
authors.initials: M
authors.lastname: Koizumi
authors.forename: Masato
authors.initials: M
authors.lastname: Yoshioka
authors.forename: Seiichi
authors.initials: S
authors.lastname: Shinji
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Yamashita
authors.forename: Takashi
authors.initials: T
authors.lastname: Tajiri
mesh_terms: 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
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D005472:Fluorouracil