Implication of thymidylate synthase in the outcome of patients with invasive ductal carcinoma of the pancreas and efficacy of adjuvant chemotherapy using 5-fluorouracil or its derivatives.

Abstract

Thymidine synthase (TS) is a key enzyme in the synthesis of pyrimidine in the de novo pathway of DNA synthesis and a major target of 5-fluorouracil (5-FU), but the implications of TS regarding human pancreatic cancer have not been reported. We assessed the expression of TS in invasive ductal carcinoma (IDC) of the pancreas by immunostaining and evaluated its clinicopathological significance, especially its implications regarding the efficacy of chemotherapy with 5-FU or its derivatives. The expression of TS in the nuclei of pancreatic cancer cells in 72 primary lesions of resectable IDC and 30 distant metastases of unresectable IDC was examined by immunostaining using anti-TS polyclonal antibody and immunoreactivity was classified into three categories: negative (-), low (+) and high (2+). High TS immunoreactivity was detected in 43% (31 of 72) of the primary lesions of the resectable IDCs and in 47% (18 of 38) of the metastatic lesions of the unresectable IDCs. The high TS in primary lesions showed a significantly inverse correlation with the level of nodal involvement. High TS immunoreactivity had a significant influence on the outcome of patients with resectable IDC and the rate of survival of the high TS immunoreactivity group was significantly higher than that of the negative or low reactivity groups, although high TS immunoreactivity did not have a significant influence on survival of the patients with unresectable IDC. The implications of TS immunoreactivity regarding the efficacy of 5-FU-based adjuvant chemotherapy (ACT) was also assessed. The high TS immunoreactivity group showed significantly better survival in both the patients who received ACT and those who were treated by surgery alone, in the resectable IDC among patients with resectable IDC. In cases of unresectable IDC, there were no differences in survival between the high and low TS groups among the patients who received ACT and those who were treated by surgery. In conclusion, high TS immunoreactivity was found to be cogent in predicting the prognosis of patients with pancreatic IDC, but its implications regarding the efficacy of 5-FU-based ACT are still unclear.