Clinical significance of the thymidylate synthase, dihydropyrimidine dehydrogenase, and thymidine phosphorylase mRNA expressions in hepatocellular carcinoma patients receiving 5-fluorouracil-based transarterial chemoembolization treatment

Hongyun Zhao,1,* Yuanyuan Zhao,2,* Ying Guo,1 Yan Huang,2 Suxia Lin,3 Cong Xue,2 Fei Xu,2 Yang Zhang,1 Liping Zhao,2 Zhihuang Hu,2 Li Zhang1,2 1State Key Laboratory of Oncology in South China and National Anti-Cancer Drug Clinical Research Centre, 2State Key Laboratory of Oncology in South China and Department of Medical Oncology, 3Department of Pathological Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China*These authors contributed equally to this workPurpose: To determine whether 5-fluorouracil (5-FU) sensitivity is associated with the mRNA expressions of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) in patients with hepatocellular carcinoma (HCC) treated with 5-FU-based transarterial chemoembolization (TACE).Methods: Formalin-fixed, paraffin-embedded tumor specimens from 40 patients treated with 5-FU-based TACE were selected for the examination of TS, DPD, and TP expression level by a quantitative real-time reverse transcription- polymerase chain reaction (PCR) technique. Patients were categorized into high and low expression groups according to the median expression level of each enzyme. Associations between the mRNA expression levels of TS, DPD, and TP and clinical parameters including treatment efficacies, clinicopathological factors, and prognosis were assessed.Results: High DPD expression was associated with worse treatment outcome, including intrahepatic disease progression rate (hazard ratio [HR] for high DPD versus low DPD, 2.212; 95% confidence interval [CI], 1.030–4.753; P = 0.042), extrahepatic disease progression rate (HR for high versus low DPD, 3.171; 95% CI, 1.003–10.023; P = 0.049), and progression-free survival (HR for high versus low DPD, 2.308; 95% CI, 1.102–4.836; P = 0.027). No correlation was found between the mRNA expression of TS/TP and treatment outcome.Conclusion: DPD mRNA expression level was negatively correlated with the clinical outcomes of HCC patients treated with 5-FU-based TACE. These results provide indirect evidence that high DPD mRNA expression is a predictive marker of treatment resistance for 5-FU.Keywords: dihydropyrimidine dehydrogenase, 5-fluorouracil, hepatocellular carcinoma, thymidylate synthase, thymidine phosphorylase, transarterial chemoembolizatio