Abstract
Objective: To analyze the impact of mRNA expression of oral fluoropyrimidine (S-1) metabolism (thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase [OPRT]), on treatment outcomes in locally advanced gastric cancer patients receiving preoperative S-1 combined with oxaliplatin chemotherapy. Methods: Preoperative stage III gastric cancer patients received S-1 (80 mg/m2/day; days 1-14) and oxaliplatin (130 mg/m2; day 1) every 3 weeks and subsequently received gastrectomy with D1/D2 lymphadenectomy. Paired tumor and normal fresh frozen tissues were collected to evaluate mRNA levels of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, and orotate phosphoribosyltransferase using quantitative reverse-transcriptase polymerase chain reaction. Results: Between December 2009 and October 2010, thirty-five patients were enrolled in this study. 24 (68.5%) patients had clinical tumor response and 10 (28.6%) patients achieved histological response. Quantitative reverse-transcriptase polymerase chain reaction results showed that orotate phosphoribo-syltransferase (OPRT) mRNA expression was significantly higher in histological responders than non-responders (3.75 vs. 1.81, P = 0.005). Diffuse-type gastric cancer patients demonstrated higher orotate phosphoribosyltransferase (OPRT) expression levels than intestinal-type ones (2.79 vs. 1.60, P = 0.014). Similar results were not found when comparing thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression levels. Conclusion: Orotate phosphoribosyltransferase (OPRT) expression level may be a potential predictive biomarker in advanced gastric cancer patients treated with oral fluoropyrimidine (S-1) based chemotherapy. Mini Abstract: Orotate phosphoribosyltransferase (OPRT) expression level may be a potential predictive biomarker in advanced gastric cancer patients treated with oral fluoropyrimidine (S-1) based chemotherapy.
Highlights
Gastric cancer is an aggressive disease with high incidence and poor prognosis in Eastern Asia, South America, Eastern Europe, and is ranked the second most common cause of cancer death [1,2]
Quantitative reverse-transcriptase polymerase chain reaction results showed that orotate phosphoribosyltransferase (OPRT) mRNA expression was significantly higher in histological responders than non-responders (3.75 vs. 1.81, P = 0.005)
We examined the expression of Thymidylate synthase (TS), Thymidine phosphlorylase (TP), dihydropyrimidine dehydrogenase (DPD) and OPRT mRNAs in fresh frozen tissues, so as to evaluate whether they are associated with chemotherapeutical treatment outcomes
Summary
Gastric cancer is an aggressive disease with high incidence and poor prognosis in Eastern Asia, South America, Eastern Europe, and is ranked the second most common cause of cancer death [1,2]. It was found that the combination of S-1 with oxaliplatin (SOX regimen) was effective for unresectable or recurrent gastric cancer patients with a tumor response rate of 59% [9] It was noted, that not all patients could benefit from S-1 based chemotherapy because of individual differences. Thymidylate synthase (TS) is an essential DNA synthesis enzyme suppressed by 5-fluoro-deoxyrudine-monophosphae (FdUMP), an active metabolite of 5-FU Expression of these enzymes, alone or in combination, have been shown to have the potential to be predictive parameters of 5-FU based chemotherapy sensitivity in gastric cancer patients [13]. There were no reports detailing 5-FU metabolic enzymes predicting chemotherapy response in advanced gastric cancer patients treated with preoperative S-1 combined with oxaliplatin chemotherapy. We examined the expression of TS, TP, DPD and OPRT mRNAs in fresh frozen tissues, so as to evaluate whether they are associated with chemotherapeutical treatment outcomes
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