Dihydropyrimidine dehydrogenase and thymidylate synthase activities in hepatocellular carcinomas and in diseased livers.

Abstract

Dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are key enzymes for predicting the efficacy of 5-FU in the treatment of malignant tumors. However, 5-FU is not commonly commonly chosen for chemotherapeutic treatment of hepatocellular carcinoma (HCC) in practice. The aim of this study was to determine the activities of both DPD and TS in HCCs and corresponding liver parenchyma and to assess the correlation between the activities of these enzymes and clinicopathological features. The possibility of using 5-FU as a first-choice chemotherapeutic agent for HCC was also evaluated. The study material comprised 33 pairs of hepatocellular carcinoma and noncancerous liver samples. The DPD and TS activities were quantified by a radiometric enzymatic assay and a 5-fluoro-2'-deoxyuridine-5'- monophosphate (FdUMP) ligand-binding assay, respectively. Pathologically invasive HCCs tended to show higher DPD activity and lower TS activity with some exceptions. DPD activity was lower in the HCCs regardless of their clinical features than in the noncancerous liver parenchyma, whereas TS activity was generally lower in HCCs except for those with certain clinical features. HCCs with multiple nodules showed lower DPD activity and those with a diameter of more than 5 cm showed lower TS activity. In the noncancerous liver parenchyma, a gradual decrease in DPD activity and an increase in TS activity were associated with the age of the patient, liver damage and z-factor. Of 30 HCC samples, 10 exhibited comparatively low DPD and TS activity, and these could be considered 5-FU-sensitive HCC. DPD and TS activity may be affected by the clinicopathological status in both the HCC and the corresponding liver parenchyma. However, further investigation is necessary. Some HCC patients may be good candidates for 5-FU-based chemotherapy based on measurements of tumor levels of DPD and TS.