Both gene expression for orotate phosphoribosyltransferase and its ratio to dihydropyrimidine dehydrogenase influence outcome following fluoropyrimidine-based chemotherapy for metastatic colorectal cancer.
Activation of 5-fluorouracil into its nucleotides requires phosphorylation by three pathways involving orotate phosphoribosyl-transferase (OPRT), uridine phosphorylase (UP), or thymidine phosphorylase (TP). In this study, we investigated the association between gene expressions of these three enzymes and antitumour effect. Gene expressions in primary colorectal tumours were analysed by a real-time reverse transcriptional-polymerase chain reaction method in 37 patients receiving oral treatment of tegafur-uracil and leucovorin for metastatic diseases. The median values of OPRT mRNA expressions were 1.39 and 0.85 for responding tumours and nonresponding tumours, respectively, showing a statistically significant difference (P=0.0008). Responding tumours had statistically lower expressions of TP mRNA than nonresponding tumours (P=0.006). However, there was no difference in UP mRNA expression between responding and nonresponding tumours. Patients with high OPRT (>/=1.0) gene expression survived longer than those with low OPRT (<1.0) expression. Dihydropyrimidine dehydrogenase (DPD) gene expressions were measured. Responding tumours had a statistically higher OPRT/DPD ratio than the nonresponding ones (P=0.003). When the median value of the OPRT/DPD ratio was selected as the cutoff value, patients with a high OPRT/DPD ratio survived statistically longer than those with a low ratio (P=0.0014). In conclusion, both the expression of OPRT gene and the OPRT/DPD ratio might be useful as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer.
Ichikawa
W
W
Second Department of Surgery, Saitama Medical School, 38, Moro-Hongo, Moroyama-cho, Iruma-gun, Saitama 350-0495, Japan. wataru@saitama-med.ac.jp
Uetake
H
H
Shirota
Y
Y
Yamada
H
H
Takahashi
T
T
Nihei
Z
Z
Sugihara
K
K
Sasaki
Y
Y
Hirayama
R
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis / Q000096:biosynthesis*; D004338:Drug Combinations; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009962:Orotate Phosphoribosyltransferase / Q000032:analysis / Q000096:biosynthesis*; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D005641:Tegafur / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome; D014498:Uracil / Q000008:administration & dosage / Q000494:pharmacology
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004338:Drug Combinations; D012333:RNA, Messenger; C096910:UFT(R) drug; D005641:Tegafur; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP); D009962:Orotate Phosphoribosyltransferase; D002955:Leucovorin