Antitumor Drugs For Fluoridated Related Gene Research

With deeper understanding of pharmacogenomics, clinical personalized medicine has become the strategy of the treatment of cancer and it was paied more and more attention. Tegafur is a prodrug, it is primarily converted to5-fluorourracil (5-FU) by CYP2A6in human liver, Then the activity product of5-FU—FdUMP,TS encoding by TYMS gene and5,10-methylene tetrahydrofolate form complexes, which hinder the synthesis of DNA and RNA. Tegafur is a broad spectrum anticancer drugs, it is mainly used in the treatment of gastric cancer, colorectal cancer and so on. Clinical data has shown that tegafur has a significant effect in treating many solid tumors and it also has better absorption, litter drug side effects when compared with the clinically important anti-cancer drug5-FU.CYP2A6is one of the cytochrome P450enzyme. It is the major drug metabolizing enzyme, about3%of clinical drugs were metabolized by CYP2A6enzyme (n>30). Research has shown that CYP2A6contains multiple variants,which affects the expression and activity of the CYP2A6and leads to individual metabolic differences of tegafur. This study constructed CYP2A6*13and CYP2A6*31variants and expressed in yeast cells. The metabolic activity of tegafur was detected with HPLC to assess the differences between CYP2A6wild-type and CYP2A6*13and CYP2A6*31variant enzymes. The results showed that the km value of CYP2A6*13on the metabolism of tegafur is40.89μ in vitro, which is higher than the wild-type km value (33.83μM), the metabolic clearance rate of CYP2A6*13becomes smaller, while the value of CYP2A6*31km is similar with the wild-type enzyme.The TS coded with TYMS is rate-limiting enzyme of DNA and RNA synthesis. Tegafur play the anti-tumor effect by blocking the nucleotide synthesis pathway. Now the study shows that the mRNA level of TYMS is closely related to tegafur’s treatment. In clinical practice, patient with lower mRNA level of TYMS has a better effect than the patient with higher mRNA level of TYMS. In this study, the extraction of total RNA and the detection of TYMS mRNA expression of were explored and optimized for tumor responses pridiction.This research detected about10patients, include everyone’s cancer and side normal tissue.The result show that the TYMS mRNA’s expression level of cancer tissue is higher than that of normal tissue both in gastric cancer’s and colorectal cancer’s patient samples.There is greatly difference between race and individuals in metabolism, this difference may cause different effects in individual drugs, toxicity and resistance degree. The study has shown that these differences are mainly caused by the difference of individual heritage. Although most difference between the individuals has been explained, there are still many unknown by people. The CYP2A6*31and CYP2A6*13have been found but not researched. So in this paper, we choose CYP2A6*31and CYP2A6*13to study on the tegafur’s metabolism clear effect in vitro, it can provide a theoretical basis for tegafur’s metabolism in vivo study. Also, detection of TYMS mRNA’s expression with RT-PCR Taqman probe assay method was proposed in this paper, this method is simple, convenient and can be used to guide tegafur’s medication in clinical.