title: Intratumoral induction of thymidylate synthase mRNA by 5-FU in colorectal cancer patients: association with survival.
abstract: Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in 5-fluorouracil (5-FU) catabolism. Thymidylate synthase (TS) is inhibited to form an inactive ternary complex by 5-fluoro-dUMP and is considered to be a target enzyme of 5-FU treatment. Two enzymes, DPD and TS, have been reported to be major determinants of individual sensitivity to 5-FU, and it has been reported that TS mRNA levels are modified by 5-FU treatment. We investigated their impact on treatment efficacy in colorectal cancer patients. TS and DPD mRNA levels, which correlated to the corresponding enzyme activities, were quantified in tumor tissues before and after treatment in 40 advanced colorectal cancer patients who had been treated with Doxifluridine (5'-DFUR) for 14 days before surgery. Furthermore inter-individual variations of TS mRNA levels after 5-FU treatment were found, and the individual TS induction varied between patients (0.2-2.4). Increased TS mRNA levels were found in 19 out of 40 cases. The samples were divided into two groups according to their TS mRNA induction (< or >1; TS/beta-actin ratio after treatment divided by values prior treatment) and compared with tumor reduction and survival. TS and DPD mRNA levels in tumor biopsies before treatment were not related to 5-FU responses by histological evaluations in this study. However the efficacy of 5-FU treatment was enhanced in patients with no or low TS mRNA induction (odds ratio: 6.2, p<0.05). Furthermore, longer periods of survival were observed in the group without increased TS mRNA levels. These findings suggest that TS mRNA was induced by 5-FU treatment, and the overall induction level varied between individuals. Therefore, the estimation of TS mRNA induction may be useful to predict the efficacy of 5-FU treatment.
authors.affiliation: Department of Surgery I, Nippon Medical School, Tokyo, Japan. motoko-t@nms.ac.jp
authors.forename: Motoko
authors.initials: M
authors.lastname: Tanaka-Nozaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Tajiri
authors.forename: Noritake
authors.initials: N
authors.lastname: Tanaka
authors.forename: Kiyonori
authors.initials: K
authors.lastname: Furukawa
authors.forename: Hideaki
authors.initials: H
authors.lastname: Takasaki
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Zenya
authors.initials: Z
authors.lastname: Naito
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Sugizaki
authors.forename: Hans F
authors.initials: HF
authors.lastname: Merk
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Blömeke
authors.forename: Shunji
authors.initials: S
authors.lastname: Kato
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality*; D018076:DNA, Complementary / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013940:Thymidylate Synthase / Q000096:biosynthesis*; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D018076:DNA, Complementary; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D005472:Fluorouracil