Thymidylate synthase gene expression in primary tumors predicts activity of s-1-based chemotherapy for advanced gastric cancer.

PURPOSE:To evaluate the association between dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) levels in primary gastric tumors and clinical response to S-1 or S-1 plus irinotecan in patients with unresectable advanced gastric cancer, and to investigate the molecular mechanism of augmented antitumor activity of the combination using human gastric cancer xenografts with high TS activity. MATERIALS AND METHODS:TS mRNA expression and DPD mRNA expression were measured by reverse transcription polymerase chain reaction in initial primary cancer biopsy specimens in 29 patients with advanced gastric cancer who had received S-1 alone (n=18) or in combination with irinotecan (n=11). In an experimental study, antitumor effects of S-1, irinotecan, and the combination were assessed in mice bearing human gastric tumors with high TS expression (4-1-ST and AZ-521 tumors) and low TS expression (SC-2 tumors), and activities of 5-fluorouracil-metabolizing enzymes were measured. RESULTS:In the clinical study, a strong statistical association between high TS expression and clinical resistance to S-1 alone was found (P = .009). In the experimental studies, S-1 plus irinotecan showed augmented antitumor activity against tumors with high TS activity (P < .01) compared with either agent alone. A potential mechanism for this effect was suggested by the significant reduction in TS activity observed following irinotecan administration in tumors with high TS activity. CONCLUSION:This study suggests that, via down-regulation of TS by irinotecan treatment, combination chemotherapy with S-1 and irinotecan could be effective in gastric cancer patients with high TS levels.