Thymidylate synthase expression in oral squamous cell carcinoma predicts response to S-1

Abstract

Abstract. The purpose of this research was to evaluate the predictive value of expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), or orotate phosphoribosyltransferase (OPRT) genes for response to S-1. Twenty-five patients with oral squamous cell carcinoma (OSCC) received S-1 80 mg/m 2 /day. Pretreatment tumor biopsies were analyzed for TS, DPD, TP or OPRT mRNA expression by real-time reverse transcription-PCR. TS protein expression was evaluated by immunohistochemistry using a polyclonal TS antibody. Twenty-five patients were evaluable for response and gene expression. Six of the 25 (24%) achieved complete remission and 4 of the 25 (16%) had a partial response. Median TS/ß-actin was 2.51 (range 0.98-7.07). Median TS/ß-actin was 1.26 in responding patients and 3.43 in non-responders (P=0.0001). Ten of 11 patients with TS/ß-actin <1.80 and 0 of 15 with higher values responded (P<0.0001). Overall survival was 29.7 months in patients with TS/ß-actin <1.80 and 41.7 months in patients with higher values (P=0.0013). No correlations were seen between expression of DPD, TP or OPRT mRNA and response or survival. Weak TS staining was seen in 6 of 25 tumors evaluable for immunohistochemistry, including 5 responders. All 4 of the patients with both weak staining and TS/ß-actin <1.80 responded. High TS mRNA expression predicts non-response to S-1. On the other hand, high levels of DPD or TP mRNA and low levels of OPRT mRNA are not associated with S-1 resistance. TS mRNA expression is considered to be a useful prognostic factor in OSCC patients with S-1 single-agent therapy.

Effects of smoking and alcohol consumption on 5-fluorouracil-related metabolic enzymes in oral squamous cell carcinoma

“…This complex inhibits the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate, which is an essential step of DNA synthesis, thus exerting anticancer effects (2). Consequently, the overexpression of TS possibly decreases the inhibitory effect of 5-FU on DNA synthesis; several studies suggested that high amounts of TS in tumor cells may decrease the efficiency of 5-FU and lead to the development of drug resistance (3)(4)(5)(6)(7). DPD is the initial and rate-limiting enzyme in the catabolic pathway of 5-FU.…”

“…1). Thus, the anticancer effects of 5-FU are closely correlated with the activity of its metabolic enzymes, which have been extensively investigated in oral cancers (3,4,8,9,11,16).…”

“…The effects of 5-FU are closely associated with the activity of its metabolic enzymes. The 5-FU-related enzymes, namely thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase (TP), play a significant role in the anticancer effects of 5-FU (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Therefore, evaluation of the mRNA expression levels of these enzymes may determine the desirable efficiency and concomitant side effects of 5-FU.…”

“…Therefore, evaluation of the mRNA expression levels of these enzymes may determine the desirable efficiency and concomitant side effects of 5-FU. From this point of view, the correlation between enzyme expression and anticancer effects has been extensively investigated (3,4,8,9,11,16). Although there are controversial points, it was suggested that the high expression of DPD in tumor tissues may reduce the anticancer effects of 17).…”

Combined evaluation of dihydropyrimidine dehydrogenase and thymidine phosphorylate mRNA levels in tumor predicts the histopathological effect of 5-fluorouracil-based chemoradiotherapy

“…In OSCCs, TS expression, but not TS, DPD or OPRT expression, was shown to predict the response to S-1 [30]. Kobayashi et al reported that DPD expression may provide a clue to predicting the sensitivity to 5-FU in patients with OSCC [29].…”