title: Intratumoral gene expression of 5-fluorouracil pharmacokinetics-related enzymes in stage I and II non-small cell lung cancer patients treated with uracil-tegafur after surgery: a prospective multi-institutional study in Japan.
abstract: OBJECTIVE
  This investigation was conducted to assess the use of the intratumoral mRNA expression levels of nucleic acid-metabolizing enzymes as biomarkers of adjuvant chemotherapy for non-small cell lung cancer (NSCLC) using uracil-tegafur in a multi-institutional prospective study.
  
  
  METHODS
  236 patients with a completely resected NSCLC (adenocarcinoma and squamous cell carcinoma) of pathological stage IA (maximum tumor diameter of 2 cm or greater), IB, and II tumors were given a dose of 250 mg of uracil-tegafur per square meter of body surface area per day orally for two years after surgery. Intratumoral mRNA levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), and thymidine phosphorylase (TP) genes relative to an internal standard, β-actin, were determined using laser-capture microdissection and fluorescence-based real time PCR detection systems.
  
  
  CONCLUSIONS
  Among 5-FU target enzymes, TS was the only one that showed a significant difference in the level of gene expression between the high and low gene expression groups, for both disease-free survival (DFS) and overall survival (OS), when patients were divided according to median values; 5-year DFS rates in high/low TS gene expression were 60.4% and 72.6%, respectively (p=0.050), 5-year OS rates were 78.1% and 88.6%, respectively (p=0.011). Cox's proportional hazard model indicated that the pathological stage and TS gene expression level were independent values for predicting DFS. The TS gene expression level was shown to be an independent predictive factor for DFS in stage I and II NSCLC patients who were treated with uracil-tegafur following surgery.
authors.affiliation: Department of General Thoracic Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan; Department of General Thoracic Surgery, Kawasaki Municipal Hospital, 12-1 Shinkawadori, Kawasaki-ku, Kawasaki, Kanagawa 210-0013, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Eguchi
authors.affiliation: Department of Pulmonology, National Hospital Organization, Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Oyama
authors.affiliation: Department of General Thoracic Surgery, Saiseikai Utsunomiya Hospital, Tochigi, 911-1 Takebayashi, Utsunomiya, Tochigi 321-0974, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.affiliation: Department of General Thoracic Surgery, Kawasaki Municipal Ida Hospital, 1272 Ida, Nakahara-ku, Kawasaki, Kanagawa 211-0035, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Abiko
authors.affiliation: Department of General Thoracic Surgery, Kawasaki Municipal Hospital, 12-1 Shinkawadori, Kawasaki-ku, Kawasaki, Kanagawa 210-0013, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sawafuji
authors.affiliation: Department of General Thoracic Surgery, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Horio
authors.affiliation: Department of General Thoracic Surgery, National Hospital Organization, Ibaraki-higashi Hospital, Ibaraki, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hashizume
authors.affiliation: Department of Surgery, School of Medicine Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Matsutani
authors.affiliation: Department of Pulmonology, National Hospital Organization, Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Kato
authors.affiliation: Department of General Thoracic Surgery, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Department of Surgery, School of Medicine Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. Electronic address: mkawamur@med.teikyo-u.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kawamura
authors.affiliation: Division of General Thoracic Surgery, School of Medicine Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kobayashi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011446:Prospective Studies; D012307:Risk Factors; D005641:Tegafur / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D005641:Tegafur
keywords: Adjuvant chemotherapy; Biomarker; Dihydropyrimidine dehydrogenase; Non-small cell lung cancer; Orotate phosphoribosyltransferase; Thymidine phosphorylase; Thymidylate synthase; Uracil-tegafur