Abstract
Fluoropyrimidine drugs (FPs), including 5-fluorouracil, tegafur, capecitabine, and doxifluridine, are among the most widely used anticancer agents in the treatment of solid tumors. However, severe toxicity occurs in approximately 30% of patients following FP administration, emphasizing the importance of predicting the risk of acute toxicity before treatment. Three metabolic enzymes, dihydropyrimidine dehydrogenase (DPD), dihydropyrimidinase (DHP), and β-ureidopropionase (β-UP), degrade FPs; hence, deficiencies in these enzymes, arising from genetic polymorphisms, are involved in severe FP-related toxicity, although the effect of these polymorphisms on in vivo enzymatic activity has not been clarified. Furthermore, the clinical usefulness of current methods for predicting in vivo activity, such as pyrimidine concentrations in blood or urine, is unknown. In vitro tests have been established as advantageous for predicting the in vivo activity of enzyme variants. This is due to several studies that evaluated FP activities after enzyme metabolism using transient expression systems in Escherichia coli or mammalian cells; however, there are no comparative reports of these results. Thus, in this review, we summarized the results of in vitro analyses involving DPD, DHP, and β-UP in an attempt to encourage further comparative studies using these drug types and to aid in the elucidation of their underlying mechanisms.
Highlights
Fluoropyrimidine drugs (FPs), including 5-fluorouracil (5-FU) and its oral prodrugs tegafur, capecitabine, and doxifluridine, are widely used in the treatment of solid tumors in the gastrointestinal tract, breast, liver, lung, head, and neck [1,2,3]
While other in vitro techniques have been used to evaluate genetic polymorphisms including gene expression profiling, in this review, we focus on the in vitro analysis of the FP-metabolizing enzymes: dihydropyrimidine dehydrogenase (DPD), DHP, and β-UP, providing further information to aid in the application of genetic testing in a clinical setting in light of recent novel insights
FPs are degraded by three metabolic enzymes (DPD, DHP, and β-UP), and a reduction or elimination of their activities leads to severe FP-related toxicity
Summary
Fluoropyrimidine drugs (FPs), including 5-fluorouracil (5-FU) and its oral prodrugs tegafur, capecitabine, and doxifluridine, are widely used in the treatment of solid tumors in the gastrointestinal tract, breast, liver, lung, head, and neck [1,2,3]. More than 500 DPYD polymorphisms to date have been identified and have been linked to FP-related toxicity in cancer patients [22,37,38,39,40,41,42,43,44,45] Several of these variants are known to alter amino acid sequence or mRNA splicing, resulting in decreased enzymatic activity. In vitro testing is one of the methods used for estimating DPD phenotypes and for the functional analysis of identified non-synonymous variants [54,55,56,57,58,59,60] Several studies of such tests using E. coli or mammalian cell expression systems have been reported (Table 1). 498G > A 524C > T 557A > G 601A > C 632A > G 703C > T (DPYD*8) 710C > T 775A > G 851G > T 868A > G 893C > T 910T > C 929T > C 934C > T 937G > T 967G > A
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