Change of TS, DPD and OPRT levels in gastric carcinoma and normal gastric mucosa after S-1-based neoadjuvant chemotherapy

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Background: S-1, a most effective dihydropyrimidine dehydrogenase (DPD)-inhibitory fluoropyrimidine derivative, used as adjuvant chemotherapy has recently been shown to improve clinical outcome in patients with stage II and III gastric carcinoma (N Engl J Med 2007; 357:1810-1820). Furthermore, S-1 associated with cisplatin has recently been shown to be more effective than S-1 alone and we have therefore adopted S-1 plus cisplatin as a primary regimen of neoadjuvant chemotherapy (NAC) for patients with advanced-stage gastric carcinoma. Thymidylate synthase (TS) and DPD are the 5-FU metabolism related enzymes that have been shown to be associated with anticancer responses and long-term clinical outcomes. Orotate phosphoribosyltransferase (OPRT) on the other hand is a primary enzyme involved in the first-step activation process of 5-fluorouracil and we have shown that OPRT levels in gastric carcinoma can predict sensitivity to 5-fluorouracil (Cancer Sci 2006; 97:492-498). We have hypothesized that response and resistance to S-1-based NAC is associated with the changes of these enzyme levels involved in 5-FU metabolism. Aims: The primary aim of the present study was to examine the changes of TS, DPD and OPRT levels in gastric carcinoma and normal gastric mucosa after S-1-based NAC. Materials and Methods: A total of 38 patients with advanced-stage gastric carcinoma who underwent surgical resection were subjected to the study. A total of 25 patients (NAC group) received NAC with the combination of S-1 (80 to 120 mg/m² per day for 4 weeks) and cisplatin (35 to 60 mg/m² on day 8) and 13 patients underwent surgery without NAC (NonNAC group). At least 2 cycles of this regimen were performed. TS, DPD and OPRT levels in gastric carcinoma and normal gastric mucosa were determined by enzyme-linked immunosorbent assays that specifically established. Results: While the TS levels in gastric carcinoma were significantly higher than those in normal gastric mucosa (46 ± 74 vs. 10 ± 9 ng/mg protein), there was no difference of DPD and OPRT between carcinoma and normal gastric mucosa. The TS levels of carcinoma in NAC group were significantly higher than those in NonNAC group (61 ± 88 vs. 18 ± 8 ng/mg protein). There was no difference of DPD levels in carcinoma between NAC group and NonNAC group (159 ± 68 vs. 175 ± 63 ng/mg protein). There was no difference of OPRT levels in carcinoma between NAC group and NonNAC group (5.1 ± 3.3 vs. 6.0 ± 3.8 ng/mg protein). Conclusion: The results that enhanced TS levels in gastric carcinoma tissue after S-1-based neoadjuvant chemotherapy may provide some insight into resistance appears after further anticancer chemotherapy with fluoropyrimidine derivatives.