Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin.
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.
Yonemori
Kan
K
Division of Hepatobiliary and Pancreatic Oncology and Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Ueno
Hideki
H
Okusaka
Takuji
T
Yamamoto
Noboru
N
Ikeda
Masafumi
M
Saijo
Nagahiro
N
Yoshida
Teruhiko
T
Ishii
Hiroshi
H
Furuse
Junji
J
Sugiyama
Emiko
E
Kim
Su-Ryang
SR
Kikura-Hanajiri
Ruri
R
Hasegawa
Ryuichi
R
Saito
Yoshiro
Y
Ozawa
Shogo
S
Kaniwa
Nahoko
N
Sawada
Jun-Ichi
J
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
D004273:DNA, Neoplasm; D005467:Floxuridine; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D002945:Cisplatin; C084565:2',2'-difluoro-2'-deoxyuridine; D000093542:Gemcitabine