title: Predictive markers of capecitabine sensitivity identified from the expression             profile of pyrimidine nucleoside-metabolizing enzymes.
abstract: Molecular markers predicting sensitivity to anticancer drugs are important             and useful not only for selecting potential responders but also for developing             new combinations. In the present study, we analyzed the difference in the sensitivity             of xenograft models to capecitabine (Xeloda®), 5'-deoxy-5-fluorouridine (5'-DFUR,             doxifluridine, Furtulon®) and 5-FU by comparing the mRNA levels of 12 pyrimidine             nucleoside-metabolizing enzymes. Amounts of mRNA in the tumor tissues of 80 xenograft             models were determined by real-time RT-PCR and mutual correlations were examined.             A clustering analysis revealed that the 12 enzymes were divided into two groups;             one group consisted of 8 enzymes, including orotate phosphoribosyl transferase             (OPRT), TMP kinase (TMPK) and UMP kinase (UMPK), and was related to the de novo             synthesis pathway for nucleotides, with mRNA expression levels showing significant             mutual correlation. In the other group, 4 enzymes, including thymidine phosphorylase             (TP) and dihydropyrimidine dehydrogenase (DPD), were involved in the salvage/degradation             pathway of the nucleotides, and the mRNA levels of this group were dispersed more             widely than that of the de novo group. Antitumor activity was assessed in 24 xenograft             models for each drug. The antitumor activity of capecitabine and 5'-DFUR correlated             significantly with the mRNA levels of TP and with the TP/DPD ratio, whereas the             activity of 5-FU correlated significantly with OPRT, TMPK, UMPK and CD. In a stepwise             regression analysis, TP and DPD were found to be independent predictive factors             of sensitivity to capecitabine and 5'-DFUR, and UMPK was predictive of sensitivity             to 5-FU. These results indicate that the predictive factors for sensitivity to             capecitabine and 5'-DFUR in xenograft models may be different from those for 5-FU,             suggesting that these drugs may have different responders in clinical usage.
authors.affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura 247-8530, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yasuno
authors.forename: Mitsue
authors.initials: M
authors.lastname: Kurasawa
authors.forename: Mieko
authors.initials: M
authors.lastname: Yanagisawa
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Sato
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.forename: Kazushige
authors.initials: K
authors.lastname: Mori
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000069287:Capecitabine; D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D005467:Floxuridine / Q000627:therapeutic use; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000378:metabolism; D013937:Thymidine Kinase / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism; D014541:Uridine Kinase / Q000378:metabolism; D014543:Uridine Phosphorylase / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D005467:Floxuridine; D003841:Deoxycytidine; D000069287:Capecitabine; D012264:Ribonucleotide Reductases; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D014543:Uridine Phosphorylase; D013939:Thymidine Phosphorylase; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D014541:Uridine Kinase; C023276:uridine monophosphate kinase; C019979:cytidylate kinase; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D003564:Cytidine Deaminase; D005472:Fluorouracil; C025034:doxifluridine