title: Impact of 5-fluorouracil metabolizing enzymes on chemotherapy in patients with resectable colorectal cancer.
abstract: Although 5-fluorouracil (5-FU) is an important drug for colorectal cancer (CRC) treatment, no useful biomarker is currently available to predict treatment response. Since 5-FU is converted into active or inactive forms by orotate phosphoribosyltransferase (OPRT) or dihydropyrimidine dehydrogenase (DPD), a correlation between these enzymes and response to 5-FU has been suggested. However, such a correlation has not been investigated prospectively. Therefore, in the present study, we aimed to prospectively evaluate whether OPRT and DPD were predictive factors of the response to 5-FU treatment in patients with resectable CRC. The present investigation was designed as a multicenter prospective cohort study. OPRT and DPD activities were assessed in biopsy samples, obtained surgically from patients with resectable CRC. The OPRT/DPD ratio was calculated and the cut-off values for this ratio were determined for 5-year disease-free survival (DFS) and overall survival (OS). Patients were treated with 5-FU/leucovorin (LV) regimens and oral 5-FU. The endpoint of this study was the correlation between the OPRT/DPD ratio and 5-year DFS and OS. The cut-off value for the OPRT/DPD ratio was determined by using the maximum χ2 statistic method against 5-year DFS and OS. Sixty-eight patients were enrolled from July 2003 to May 2005. The median follow-up period was 1925 days. The OPRT/DPD ratio cut-off values for 5-year DFS and OS were 0.015 and 0.013, respectively. During the 5-year DFS and OS periods, patients with higher cut-off values had a better prognosis than those with lower ratios (P=0.03 and 0.02, respectively). In conclusion, our results suggest that the OPRT/DPD ratio could be a predictive factor for response to 5-FU/LV adjuvant chemotherapy.
authors.affiliation: Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Ochiai
authors.affiliation: Department of Surgery, Hyogo Prefectural Awaji Medical Center, Hyogo 656-0021, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Umeki
authors.affiliation: Department of Surgery, Kasukabe Municipal Hospital, Saitama 344-0067, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.affiliation: Department of Surgery, Nishimino Kosei Hospital, Gifu 503-131, Japan.
authors.forename: Tatsumi
authors.initials: T
authors.lastname: Iida
authors.affiliation: Department of Surgery, Hitachi General Hospital, Ibaragi 317-0077, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Okumura
authors.affiliation: Department of Surgery, Matsudo City Hospital, Chiba 271-0064, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Department of Surgery, Mitsui Memorial Hospital, Tokyo 101-8643, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Sakamoto
authors.affiliation: Department of Surgery, Kure Kyosai Hospital, Hiroshima 737-0811, Japan.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Miyoshi
authors.affiliation: Department of Surgery, Hokkaido P.W.F.A.C Asahikawa-Kosei General Hospital, Hokkaido 078-8211, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Surgery, Koshigaya Municipal Hospital, Saitama 343-0023, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Tsumura
authors.affiliation: Department of Surgery, Japanpost Osaka-kita Teishin Hospital, Osaka 530-0016, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Tokunaga
authors.affiliation: Department of Surgery, Hokkaido Cancer Center, Hokkaido 003-0804, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Naitou
authors.affiliation: Department of Surgery, Kariya Toyota General Hospital, Aichi 448-8505, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Fukui
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism*; D011446:Prospective Studies; D016019:Survival Analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D009962:Orotate Phosphoribosyltransferase; D002955:Leucovorin; D005472:Fluorouracil