Thymidylate Synthase Gene Expression in Primary Tumors Predicts Activity of S-1–Based Chemotherapy for Advanced Gastric Cancer

摘要

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 1 – 4 and tumor levels of dihydropyrimidine dehydrogenase (DPD), a rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism, have been reported to inversely correlate with sensitivity to 5-FU– based chemotherapy. 5 – 9 These observations have led to attempts to predict efficacy of 5-FU treatment by assessing TS and DPD levels in gastrointestinal tumors. 5 , 8 – 11 S-1 is a new oral fluoropyrimidine with high activity in gastric and colorectal cancer. 12 – 14 The drug contains the potent DPD inhibitor 5-chloro-2, 4-dihydroxypyrimidine (gimeracil, CDHP) and a potassium oxonate (oteracil potassium, Oxo) component that inhibits the phosphorylation of 5-FU, together with the 5-FU prodrug tegafur. The inclusion of CDHP as a component of S-1 is expected to reduce the effect of level of DPD expression on tumor response to fluoropyrimidine treatment. However, as with other fluoropyrimidines, tumors that express high levels of TS mRNA are expected to be relatively resistant to S-1. Ichikawa et al 15 reported a positive correlation between TS mRNA expression and expression of topoisomerase I, and Danenberg et al 16 have reported cases of metastatic colorectal cancer in which the topoisomerase I inhibitor irinotecan was effective in tumors with high levels of TS mRNA. Such findings suggest that the use of irinotecan in combination with S-1 might overcome tumor fluoropyrimidine resistance on the basis of high TS levels, and that selection of S-1 monotherapy or combined therapy could be made on the basis of tumor TS mRNA levels. In the current study, we analyzed TS mRNA and DPD mRNA levels in initial biopsy samples from patients with unresectable advanced gastric cancer who had been treated with S-1 monotherapy or S-1 plus irinotecan to determine the association of expression levels with response to treatment. We further evaluated the antitumor activity of S-1 plus irinotecan using human gastric cancer xenografts with high or low TS activity in nude mice and investigated the molecular mechanism of the augmented activity seen with the combination.