title: Orotate phosphoribosyltransferase expression level in tumors is a potential determinant of the efficacy of 5-fluorouracil.
abstract: Although the intratumoral expression levels of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are known to affect the antitumor activity of 5-fluorouracil (5-FU), the importance of orotate phosphoribosyltransferase (OPRT) has remained unclear. This study investigated the relationship between intratumoral OPRT expression and the antitumor activity of 5-FU using human NCI60 cell lines with similar levels of TS and DPD messenger RNAs, as well as 31 tumor xenografts. The OPRT mRNA level was positively correlated with the 5-FU efficacy in these cell lines. In vitro, the 50% growth-inhibitory concentrations of 5-FU were closely correlated with the OPRT mRNA levels in cancer cell lines with similar levels of TS mRNAs when combined with a DPD inhibitor. Moreover, downregulation of OPRT with small-interfering RNA decreased the sensitivities of the cultured tumor cells to 5-FU. These results suggest that the OPRT expression level in tumors is an additional determinant of the efficacy of 5-FU.
authors.affiliation: Personalized Medicine Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima 771-0194, Japan. etsu-toda@taiho.co.jp
authors.forename: Etsuko
authors.initials: E
authors.lastname: Sakamoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Nagase
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobunai
authors.forename: Shinji
authors.initials: S
authors.lastname: Oie
authors.forename: Toshinori
authors.initials: T
authors.lastname: Oka
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fukushima
authors.forename: Tatsuzo
authors.initials: T
authors.lastname: Oka
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D005472:Fluorouracil / Q000008:administration & dosage*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D009962:Orotate Phosphoribosyltransferase; D005472:Fluorouracil