title: Genetic polymorphisms of enzymes related to oral tegafur/uracil therapeutic efficacy in patients with hepatocellular carcinoma.
abstract: Oral tegafur/uracil therapy has been indicated for patients with hepatocellular carcinoma (HCC) and is often used as a single-agent treatment. However, how the treatment efficacy is related to 5-fluorouracil (5-FU) metabolic enzymes is unclear. We investigated genetic polymorphisms of the 5-FU metabolic enzymes in Japanese patients with HCC. We examined two genetic polymorphisms of the metabolic enzymes cytochrome P450 2A6 (CYP2A6) and dihydropyrimidine dehydrogenase (DPD) in 58 Japanese hepatitis C virus-seropositive HCC patients. To measure efficacy, we investigated genetic polymorphisms of the variable number of tandem repeats (VNTRs) of thymidylate synthase (TS) and classified the genotypes as high or low expression types. The frequency of the CYP2A6*4 allele (no-activity allele) among 58 HCC patients was 0.233 and a homozygous genotype (*4/*4) was found in five patients. The heterozygous genotype (T/C) of DPYD*9 (T85C) was detected in eight patients and the frequency of the DPYD*9 allele among 58 HCC patients was 0.069. Of 58 patients, 42 were classified as high expression type and 16 as low expression type for TS VNTR. Fifteen of these 16 patients appeared to have normal CYP2A6 metabolic activity and 13 of these 15 patients likely had normal DPD metabolic activity. Only 13 of 58 HCC patients (22.4%) tested may respond positively to treatment with oral tegafur/uracil. 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.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Daisan Hospital, The Jikei University School of Medicine, Komae, Tokyo, Japan. fushiya@jikei.ac.jp
authors.forename: Nao
authors.initials: N
authors.lastname: Fushiya
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takagi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Nishino
authors.forename: Setsuko
authors.initials: S
authors.lastname: Akizuki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ohnishi
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D065637:Cytochrome P-450 CYP2A6; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics*; D005838:Genotype; D006526:Hepatitis C / Q000378:metabolism; D006801:Humans; D007564:Japan; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D018598:Minisatellite Repeats; D011110:Polymorphism, Genetic; D005641:Tegafur / Q000008:administration & dosage; D013940:Thymidylate Synthase / Q000235:genetics; D014498:Uracil / Q000008:administration & dosage
chemical_list: D005641:Tegafur; D014498:Uracil; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil