title: Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin.
abstract: OBJECTIVE
  We investigated single-nucleotide polymorphisms of the cytidine deaminase gene (CDA), which encodes an enzyme that metabolizes gemcitabine, to clarify the relationship between the single-nucleotide polymorphism 208G>A and the pharmacokinetics and toxicity of gemcitabine in cancer patients treated with gemcitabine plus cisplatin.
  
  
  METHODS
  Six Japanese cancer patients treated with gemcitabine plus cisplatin were examined. Plasma gemcitabine and its metabolite 2',2'-difluorodeoxyuridine were measured using an high-performance liquid chromatography method, and the CDA genotypes were determined with DNA sequencing.
  
  
  RESULTS
  One patient, a 45-year-old man with pancreatic carcinoma, showed severe hematologic and nonhematologic toxicities during the first course of chemotherapy with gemcitabine and cisplatin. The area under the concentration-time curve value of gemcitabine in this patient (54.54 microg hour/mL) was five times higher than the average value for five other patients (10.88 microg hour/mL) treated with gemcitabine plus cisplatin. The area under the concentration-time curve of 2',2'-difluorodeoxyuridine in this patient (41.58 microg hour/mL) was less than the half of the average value of the five patients (106.13 microg hour/mL). This patient was found to be homozygous for 208A (Thr70) in the CDA gene, whereas the other patients were homozygous for 208G (Ala70).
  
  
  CONCLUSIONS
  Homozygous 208G>A alteration in CDA might have caused the severe drug toxicity experienced by a Japanese cancer patient treated with gemcitabine plus cisplatin.
authors.affiliation: Division of Hepatobiliary and Pancreatic Oncology and Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Yonemori
authors.forename: Hideki
authors.initials: H
authors.lastname: Ueno
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ikeda
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
authors.forename: Emiko
authors.initials: E
authors.lastname: Sugiyama
authors.forename: Su-Ryang
authors.initials: SR
authors.lastname: Kim
authors.forename: Ruri
authors.initials: R
authors.lastname: Kikura-Hanajiri
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Hasegawa
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Shogo
authors.initials: S
authors.lastname: Ozawa
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005076:Exanthema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced; D020641:Polymorphism, Single Nucleotide; D013280:Stomatitis / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D004273:DNA, Neoplasm; D005467:Floxuridine; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D002945:Cisplatin; C084565:2',2'-difluoro-2'-deoxyuridine; D000093542:Gemcitabine