Elevated levels of mRNAs encoding dihydropyrimidine dehydrogenase and thymidylate synthase are associated with improved survival of patients with hepatocellular carcinoma treated with S-1.
Our study for the first time demonstrates the association of SNPs in TYMS gene and clinical outcome of HCC, suggesting that rs523230 and rs9967368 in TYMS gene might be used to predict clinical outcome of Chinese HCC patients.
Our results indicate that SAHA and 5-FU act synergistically to inhibit cell growth and tumorigenicity in HCC via the induction of cell-cycle arrest and apoptosis through a mechanism involving the inhibition of thymidylate synthase, suggesting that combination treatment with 5-FU and SAHA may be beneficial for the treatment of inoperable HCC.
Therefore, when administering oral 5-FU in patients with HCC, it is important to consider three genetic polymorphisms (CYP2A6, DPYD, and TS) associated with 5-FU metabolic enzymes.
In both the Los Angeles and Guangxi studies, low-activity genotypes (reduced enzymatic activities) of methylenetetrahydrofolate reductase (MTHFR) and high-activity genotypes (enhanced enzymatic activities) of thymidylate synthase (TYMS), both of which discourage the misincorporation of uracil into DNA, were shown to be associated with a reduced risk for HCC.
This study supports the hypothesis that reduced MTHFR activity and enhanced TYMS activity, both of which are essential elements in minimizing uracil misincorporation into DNA, may protect against the development of HCC.
The relative mRNA level of orotate phosphoribosyltransferase (OPRT), ribonucleotide reductase (RNR), dihydropyrimidine dehydrogenase (DPD) and target enzyme thymidylate synthase (TS), were analyzed in 30 matched samples of HCC (T) and non-tumor tissue (NT) using quantitative RT-PCR.
This study supports the hypothesis that reduced MTHFR activity and enhanced TYMS activity, both of which are essential elements in minimizing uracil misincorporation into DNA, may protect against the development of HCC.